CN102725305A - Melanocortin-1 receptor-specific cyclic peptides - Google Patents

Abstract

Melanocortin receptor-specific cyclic peptides of the formula (I) where R1, R2, R3, R4, R5, R6, R7, R8 and R9 are as defined in the specification, compositions and formulations including the peptides of the foregoing formula or salts thereof, and methods of preventing, ameliorating or treating melanocortin-1 receptor-mediated or responsive diseases, indications, conditions and syndromes.

Description

melanocortin-1 receptor-specific cyclic peptide

Cross References to Related Applications

This application claims priority and benefit to U.S. Provisional Patent Application Serial No. 61/263,490, filed November 23, 2009, entitled "Melanocortin-1 Receptor-Specific Cyclic Peptides" , the specification and claims of which are hereby incorporated by reference. the

Background of the invention

Field of Invention (Technical Field)

The present invention relates to melanocortin receptor-specific cyclic peptides, especially cyclic peptides selective and specific for melanocortin-1 receptors, which can be used in the treatment of melanocortin-1 Diseases, indications, conditions and syndromes mediated or responded to by receptors. the

Related technical notes:

The following discussion cites certain publications by author and year of publication, and certain publications are not considered prior art to the present invention due to recent publication dates. The discussion of these publications here is to give a more complete background and should not be construed as an admission that these publications are prior art for patentability purposes. the

A family of melanocortin receptor types and subtypes has been identified. Receptor types include the melanocortin-1 (MC-1) receptor (MCR-1), which is generally known to be expressed in normal human melanocytes and on melanoma cells, but has also been reported Expressed in various other cells including those involved in the immune response such as monocytes, neutrophils, lymphocytes, dendritic cells, natural killer (NK) cells and endothelial cells. See generally, Kang, L. et al., "A selective small molecule agonist of melanocortin-1 receptor inhibits lipopolysaccharide-induced cytokine accumulation and leukocyte infiltration in mice." receptor inhibits lipopolysaccharide-induced cytokine accumulation and leukocyte infiltration in mice" (J.Leuk.Biol. 80:897-904(2006)), and references cited therein. A number of human MCR-1 subtypes and variants are known, including those disclosed in US Patent Nos. 6,693,184 and 7,115,393. In addition to MCR-1, other melanocortin receptor types include ACTH (adrenocorticotropic hormone) melanocortin-2 receptor (MCR-2) expressed in cells of the adrenal gland, mainly in the hypothalamus, midbrain and Melanocortin-3 and melanocortin-4 (MC-4) receptors (MCR-3 and MCR-4) expressed in cells of the brainstem, and melanocortin-5 widely distributed in peripheral tissues receptor (MCR-5). the

The major endogenous melanocortin agonist is the cyclic alpha-melanostimulating hormone ("alpha-MSH") peptide. Melanocortin receptor-specific peptides typically contain the central tetrapeptide sequence His ⁶ -Phe ⁷ -Arg ⁸ -Trp ⁹ (SEQ ID NO: 1) of native α-MSH or a mimetic or variant thereof comprising one or more Various substitutions at each position (see, e.g., "Alpha-Melanotropin: the minimal active sequence in the frog skin bioassay) by Hruby, VJ et al. (Pharmaceuticals Journal of Chemistry (J.Med.Chem.), 30:2126-2130 (1987)); Castrucci, AML et al. "Alpha-Melanotropin: the minimal active sequence in lizard skin bioassays (Alpha-Melanotropin: the minimal active sequence in the lizard skin bioassay)"(Gen.Comp.Endocrinol.,73:157-163(1989)); Haskell-Luevano, C. et al. "Prototype peptoids in human melanocortin receptors MC1R and MC4R Agonists (Discovery of prototype peptidomimetic agonists at the human melanocortin receptors MC1R and MC4R)" (Journal of Medicinal Chemistry (J.Med.Chem.), 40:2133-2139 (1997)); Holder, JR et al. Melanocortin tetrapeptide Ac-His-DPhe-Arg-Trp-NH ₂ .1. Structure-activity relationships of the melanocortin tetrapeptide Ac-His-DPhe-Arg-Trp-NH modified on the histidine position _{2.1.Modifications} at the His position)" (J.Med.Chem., 45:2801-2810(2002)); Abdel-Malek, ZA et al. "Based on the use of immune Melanoma prevention strategy based on using tetrapeptide α-MSH analogs that protect human melanocytes fro m UV-induced DNA damage and cytotoxicity)” (Journal of Federation of American Societies for Experimental Biology (FASEB J.), 20:E888-E896(2006)); Bednarek, MA et al. Cyclic analogs of α-melanocyte-stimulating hormone (αMSH) with high agonist potency and selectivity at human melanocortin receptor 1b"( Peptides, 29:1010-1017 (2008)); Koikov, LN et al. "The subnanomolar hMC 1R agonist LK-184 [Ph(CH ₂ ) ₃ CO-His-D-Phe-Arg -An analogue of Trp-NH ₂ ]. An additional binding site with the human melanocortin receptor 1" (Bioorg.Med.Chem.Lett.) 14:3997- 4000 (2004)); and "Alpha-MSH tripeptide analogs activate the melanocortin-1 receptor and reduce UV-induced DNA damage in human melanocytes" by Abdel-Malek, ZA et al. 1 receptor and reduce UV-induced DNA damage in human melanocytes)” (Pigment Cell Melanoma Res. 22:635-44(2009)).

声称对一种或多种黑皮质素受体特异的肽或肽样化合物披露于美国专利号5,576,290、5,674,839、5,683,981、5,714,576、5,731,408、6,051,555、6,054,556、6,284,735、6,350,430、6,476,187、6,534,503、6,600,015、6,613,874、 6,693,165、6,699,873、6,887,846、6,951,916、7,008,925、7,049,398、7,084,111、7,176,279、7,473,760和7,582,610；美国已经公开的专利申请公开号2001/0056179、2002/0143141、2003/0064921、2003/0105024、2003/0212002、2004/ 0023859、2005/0130901、2005/0187164、2005/0239711、2006/0105951、2006/0111281、2006/0293223、2007/0027091、2007/0105759、2007/0123453、2007/0244054、2008/0039387和2009/0069242； and International Patent Application Nos. WO 98/27113, WO 99/21571, WO 00/05263, WO 99/54358, WO 00/35952, WO 00/58361, WO 01/30808, WO 01/52880, WO 01/74844, WO 01/85930, WO 01/90140, WO 02/18437, WO 02/26774, WO 03/006604, WO 2004/046166, WO 2005/000338, WO 2005/000339, WO 2005/000877, WO 2005/030797, WO 2005/060985, WO 2006/048449, WO 2006/048450, WO 2006/048451, WO 2006/048452, WO 2006/097526, WO 2007/008684, WO 2007/008704, WO 2001/009809 and 1 WO 2007/009809. the

Despite the intense scientific and pharmaceutical interest in melanocortin receptor-specific peptides, there remains a need for highly selective and specific MCR-1 agonist peptides for pharmaceutical applications. The present invention has been made against this background. the

Brief description of the invention

On the one hand, the invention provides a kind of cyclic peptide of formula (I):

including all enantiomers, stereoisomers or diastereomers thereof, or a pharmaceutically acceptable salt of any of the foregoing compounds,

in:

R ₁ is -H, -NH-R ₁₀ , -NH-R ₁₀ -R ₁₁ or -NH-R ₁₁ ;

R ₂ is -CH- or -N-;

R ₃ is -H, -CH ₃ or -CH ₂ -, and if R ₃ is -CH ₂ -, it forms a ring with R ₄ having the general structure

R ₄ is -H, if R ₃ is -CH ₂ -, R ₄ is -(CH ₂ ) _z -, and if R ₄ is -(CH ₂ ) _z -, it forms the ring with R ₃ where -( Any H in CH ₂ ) _z - is optionally substituted with R ₁₂ , or R ₄ is -(CH ₂ ) _w -R ₁₃ -(CH ₂ ) _w -R ₁₄ , where any H in (CH ₂ ) _w optionally substituted with -(CH ₂ ) _w -CH ₃ ;

R ₅ is -(CH ₂ ) _w -R ₁₅ ;

R ₆ is -H, -CH ₃ or -CH ₂ -, and if R ₆ is -CH ₂ -, it forms a ring with the general structure with R ₇

If R ₆ is -CH ₂ -, R ₇ is -(CH ₂ ) _z -, and if R ₇ is -(CH ₂ ) _z -, it forms the ring with R ₆ , or R ₇ is -(CH ₂ ) _w -R ₁₆ ;

R ₈ is -R ₁₇ -R ₁₈ or -R ₁₈ ;

_R9 is

-(CH ₂ ) _x -C(=O)-NH-(CH ₂ ) _y -,

-(CH ₂ ) _x -NH-C(=O)-(CH ₂ ) _y -,

-(CH ₂ ) _x -C(=O)-(CH ₂ ) _z -C(=O)-(CH ₂ ) _y -,

-(CH ₂ ) _x -C(=O)-NH-C(=O)-(CH ₂ ) _y -,

-(CH ₂ ) _x -NH-C(=O)-NH-(CH ₂ ) _y -,

-(CH ₂ ) _x -NH-C(=O)-(CH ₂ ) _z -C(=O)-NH-(CH ₂ ) _y -, or

-(CH ₂ ) _x -SS-(CH ₂ ) _y -;

R ₁₀ is from one to three amino acid residues;

R ₁₁ is H or a C ₁ to C ₁₇ acyl group, wherein the C ₁ to C ₁₇ comprises a linear or branched chain alkyl, cycloalkyl, alkylcycloalkyl, aryl or alkylaryl;

R ₁₂ is optionally present, and if present, in each instance R ₁₂ is independently -R ₁₃ -(CH ₂ ) _w -R ₁₄ ;

R ₁₃ is optionally present, and if present, in each instance R ₁₃ is independently

-O-,

-S-,

-NH-,

-S(=O) ₂ -,

-S(=O)-,

-S(=O) ₂ -NH-,

-NH-S(=O) ₂ -,

-C(=O)-,

-C(=O)-O-,

-O-C(=O)-,

-NH-C(=O)-O-,

-O-C(=O)-NH-,

-NH-C(=O)-, or

-C(=O)-NH-;

In each case R ₁₄ is independently -H, -CH ₃ , -N(R _19a )(R _19b ), -NH-(CH ₂ ) _z -N(R _19a )(R _19b ), -NH- CH(=NH)-N(R _19a )(R _19b ), -NH-CH(=O)-N(R _19a )(R _19b ), -O(R _19a ), -(R _19a )(R _19b ), -S(=O) ₂ (R _19a ), -C(=O)-O(R _19a ),

wherein any ring in _R is optionally substituted with one or more ring substituents, and when one or more substituents are present, the substituents are the same or different and are independently hydroxyl, halogen, sulfonamide, alkyl , -O-alkyl, aryl, -O-aryl, C(=O)-OH or C(=O)-N(R _19a )(R _19b );

R ₁₅ is phenyl, naphthyl or pyridyl, optionally substituted with one or more substituents independently selected from halogen, (C ₁ -C ₁₀ )alkyl halides, (C ₁ -C ₁₀ ) alkyl, (C ₁ -C ₁₀ ) alkoxy, (C ₁ -C ₁₀ ) alkylthio, aryl, aryloxy, nitro, nitrile, sulfonamide, amino, monosubstituted amino, bis Substituted amino, hydroxyl, carboxyl and alkoxy-carbonyl groups;

R ₁₆ is -H, -N(R _19a )(R _19b ), -NH-(CH ₂ ) _z -N(R _19a )(R _19b ), -NH-CH(=NH)-N(R _19a ) (R _19b ), -NH-CH(=O)-N(R _19a )(R _19b ), -O(R _19a ), a straight or branched C ₁ to C ₁₇ alkyl chain, -C(= O)-N(R _19a )(R _19b ), -S(=O) ₂ (R _19a ),

wherein any ring is optionally substituted with one or more optional ring substituents which, when present, are the same or different and are independently hydroxyl, halogen, sulfonamide, alkyl , -O-alkyl, aryl, aralkyl, O-aralkyl or -O-aryl;

R ₁₇ is from one to three amino acid residues;

R ₁₈ is -OH, -N(R _19a )(R _19b ), -N(R _19a )(CH ₂ ) _w -(C ₁ -C ₇ )cycloalkyl or -O-(CH ₂ ) _w -( C ₁ -C ₇ ) cycloalkyl;

R _19a and R _19b are each independently H or a C ₁ to C ₄ linear or branched alkyl chain;

in each case w is independently 0 to 5;

x is 1 to 5;

y is 1 to 5; and

z is independently 1 to 5 in each case. the

In the cyclic peptide of formula (I), R ₁₇ can be a single amino acid residue of the formula

where _R20 is

Optionally substituted with one or more ring substituents which, when present, are the same or different and are independently hydroxy, halogen, sulfonamide, alkyl, -O-alkyl, aryl or -O-aryl. the

In another aspect, there is provided a cyclic peptide of formula (II):

Wherein the variables are as specified in formula (I). _0}

In another aspect, there is provided a cyclic peptide of formula (III):

wherein in each case R _21a , R _21b and R _21c are independently hydrogen, halogen, (C ₁ -C ₁₀ )alkylhalide, (C ₁ -C ₁₀ )alkyl, (C ₁ -C ₁₀ )alk Oxy, (C ₁ -C ₁₀ )alkylthio, aryl, aryloxy, nitro, nitrile, sulfonamide, amino, monosubstituted amino, disubstituted amino, hydroxyl, carboxyl or alkoxy-carbonyl , and all other variables are as specified in formula (I).

In another aspect, there is provided a cyclic peptide of formula (IV):

Wherein R ₂₂ is H or a C ₁ to C ₉ straight or branched chain alkyl, cycloalkyl, alkylcycloalkyl, aryl or alkylaryl;

R _21a , R _21b and R _21c are as defined in formula (III); and

All other variables are as specified in formula (I). the

In another aspect, there is provided a cyclic peptide of formula (V):

wherein the variables are as specified for the cyclic peptide of formula (IV). the

In another aspect, there is provided a cyclic peptide of formula (VI):

wherein the variables are as specified for the cyclic peptide of formula (III). the

In the cyclic peptide of formula (I), R ₉ may be -(CH ₂ ) _x -C(=O)-NH-(CH ₂ ) _y -, wherein x is 4 and y is 3, wherein x is 3 and y is 2, or where x is 2 and y is 1. Alternatively, R ₉ may be -(CH ₂ ) _x -NH-C(=O)-(CH ₂ ) _y -, where x is 1 and y is 2, where x is 2 and y is 3, or where x is 3 and y is 4.

其中z是3。  In cyclic peptides of formula (I), R ₃ can form a ring with R ₄ having the general structure

where z is 3.

In the cyclic peptides of formula (I), R ₁₇ may be a single amino acid residue of formula.

In another aspect, the present invention provides a pharmaceutical composition based on melanocortin receptor-specific peptides for the treatment of melanocortin receptor-mediated diseases, indications, disorders and syndromes. the

In another aspect, the present invention provides a peptide-based melanocortin receptor-specific drug for use in the treatment of MCR-1 related disorders, diseases, indications, conditions and/or syndromes, wherein said peptide is a A selective MCR-1 ligand. the

In another aspect, the invention provides peptides that are specific for the melanocortin receptor MCR-1 and are agonists. the

In another aspect, the present invention provides a melanocortin receptor-specific drug for treatment, wherein the way of administration for treatment is via pulmonary administration. the

In another aspect, the present invention provides specific MCR-1 cyclic peptides that are effective over a significant dosage range. the

Yet another aspect of the present invention provides specific MCR-1 cyclic peptides which, due to their high potency at low doses, can be administered by delivery systems other than conventional intravenous, subcutaneous or intramuscular injections, including but not Limited to oral delivery systems, inhalational delivery systems, pulmonary delivery systems, nasal delivery systems, and transmucosal delivery systems. the

Additional aspects and novel features and further applicability of the invention are set forth in part in the detailed description which follows, and will become apparent to those skilled in the art upon examination, or may be learned by practice of the invention. Aspects of the invention may be realized and attained by means of the instrumentalities and combinations particularly pointed out in the appended claims. the

Detailed description of the invention

1.0 Definitions

Before proceeding with the description of the present invention, certain terms are as defined as set forth herein. the

In the sequences given for the peptides according to the invention, the amino acid residues have their conventional meanings as given in Chapter 2400 of the Eighth Edition of the Manual of Patent Examining Procedure . Thus, "Nle" is norleucine, "Asp" is aspartic acid, "His" is histidine, "Phe" is phenylalanine, "Arg" is arginine, and "Trp" is tryptophan acid, and "Lys" is lysine, and so on. It will be appreciated that the "D" isomer is designated with a "D-" before the three letter code or amino acid name, eg D-Phe is D-phenylalanine. Amino acid residues not covered by the foregoing have the following definitions:

An "α,α-disubstituted amino acid" means any α-amino acid having another substituent at the α position, which substituent may or may not be identical to the side chain portion of the α-amino acid. In addition to the side chain portion of the α-amino acid, suitable substituents include C ₁ to C ₆ straight or branched chain alkyl groups. Aib is an example of an α,α-disubstituted amino acid. However, α,α-disubstituted amino acids can be referred to using conventional L- and D-isomeric references, with the understanding that these references are for convenience and that when the substituents at the α position differ, this amino acid can Alternatively referred to as an α,α-disubstituted amino acid derived from the appropriate L- or D-isomer of a residue with the indicated amino acid side chain moiety. Thus (S)-2-amino-2-methylhexanoic acid can be called an α,α-disubstituted amino acid derived from L-Nle or an α,α-disubstituted amino acid derived from D-Ala. Similarly, Aib can be referred to as an α,α-disubstituted amino acid derived from Ala. Whenever an α,α-disubstituted amino acid is provided, it is understood to include all (R) and (S) configurations thereof. Whenever the claims or specification herein refer to an "amino acid", such designation includes, but is not limited to, an "α,α-disubstituted amino acid".

An "N-substituted amino acid" means any amino acid in which one amino acid side chain moiety is covalently bonded to a backbone amino group, optionally including no substituents other than H at the alpha carbon position. Sarcosine is an example of an N-substituted amino acid. As an example, sarcosine can be called an N-substituted amino acid derivative of Ala, because sarcosine and Ala have the same amino acid side chain part, both of which are methyl groups. Whenever an "amino acid" is referred to in the claims or specification herein, such designation includes, but is not limited to, an "N-substituted amino acid". the

In some cases, a group can replace an amino acid, for example specifically using a dicarboxylic acid instead of an amino acid. One particular dicarboxylic acid used herein is succinic acid, abbreviated "Suc", having the formula

The term "alkane" includes straight or branched chain saturated hydrocarbons. Straight Examples of alkane groups include methane, ethane, propane, and the like. Examples of branched or substituted alkane groups include methyl butane or dimethyl butane, methyl pentane, dimethyl pentane or trimethyl pentane, and the like. In general, any alkyl group may be a substituent of an alkane.

The term "olefin" includes unsaturated hydrocarbons containing one or more double carbon-carbon bonds. Examples of such olefinic groups include ethylene, propylene, and the like. the

The term "alkenyl" includes a linear monovalent hydrocarbon group of 2 to 6 carbon atoms or a branched monovalent hydrocarbon group of 3 to 6 carbon atoms containing at least one double bond; examples thereof include vinyl, 2-propenyl and the like. the

"Alkyl" groups designated herein include those alkyl groups of the specified length in a straight or branched configuration. Examples of such alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl, pentyl, isopentyl, hexyl, isohexyl and the like. the

The term "alkyne" includes a linear monovalent hydrocarbon group of 2 to 6 carbon atoms or a branched monovalent hydrocarbon group of 3 to 6 carbon atoms containing at least one triple bond; examples thereof include acetylene, propyne, butyne and the like. the

The term "aryl" includes a monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 12 ring atoms, optionally substituted independently with one or more substituents selected from the group consisting of alkyl, haloalkyl, cycloalkyl , alkoxy, alkylthio, halogen, nitro, acyl, cyano, amino, monosubstituted amino, disubstituted amino, hydroxy, carboxy or alkoxy-carbonyl. Examples of an aryl group include phenyl, diphenyl, naphthyl, 1-naphthyl and 2-naphthyl, derivatives thereof, and the like. the

The term "aralkyl" includes the radical ^-RaRb , where ^Ra is an alkenyl (a divalent alkyl) group and ^Rb is an aryl group as defined ^above . Examples of aralkyl groups include benzyl, phenethyl, 3-(3-chlorophenyl)-2-methylpentyl and the like.

The term "aliphatic" includes compounds having hydrocarbon chains, such as alkanes, alkenes, alkynes and derivatives thereof. the

The term "acyl" includes a group R(C=O)-, where R is an organic group. An example is the acetyl group _CH3 -C(=O)-, referred to herein as "Ac". As used herein, R may comprise a C ₁ to C ₁₇ straight or branched chain alkyl, cycloalkyl, alkylcycloalkyl, aryl or alkylaryl.

A peptide or aliphatic moiety is "acylated" when an alkyl or substituted alkyl group as defined above is bonded through one or more carbonyl {-(C=O)-} groups. A peptide is mostly acylated at the N-terminus. the

An "omega-aminoaliphatic chain" comprises an aliphatic moiety having a terminal amino group. Examples of ω-aminoaliphatic chains include aminoheptanoyl and the amino acid side chain moieties of ornithine and lysine. the

The term "heteroaryl" includes monocyclic and bicyclic aromatic rings containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur. 5- or 6-membered heteroaryl is a monocyclic heteroaromatic ring; examples include thiazole, oxazole, thiophene, furan, pyrrole, imidazole, isoxazole, pyrazole, triazole, thiadiazepine, tetrazole, oxadiazole Azole, pyridine, pyridazine, pyrimidine, pyrazine, etc. Bicyclic heteroaromatic rings include, but are not limited to, benzothiadiazole, indole, benzothiophene, benzofuran, benzimidazole, benzisoxazole, benzothiazole, quinoline, benzotriazole, benzo oxazoles, isoquinolines, purines, furopyridines and thienopyridines. the

"Amide" includes compounds having a trivalent nitrogen (-C(=O) _-NH2 ) attached to a carbonyl group, such as methylamine, ethylamine, propylamine, and the like.

"Imide" includes compounds containing an imide group (-C(=O)-NH-C(=O)-). the

An "amine" includes compounds containing an amino group (-NH ₂ ).

A "nitrile" includes compounds containing a (-CN) group bonded to an organic group. the

The term "halogen" includes halogen atoms fluorine, chlorine, bromine and iodine, and groups including one or more halogen atoms, such as _-CF3 and the like.

The term "composition", such as a pharmaceutical composition, covers a product comprising an active ingredient together with an inert ingredient constituting a carrier, as well as any composition resulting, directly or indirectly, from the combination, complexation or aggregation of two or more ingredients. product, or any product resulting from the dissociation of one or more components, or from any other type of reaction or interaction of one or more components. Accordingly, pharmaceutical compositions used in the present invention include any composition produced by admixing an active ingredient and one or more pharmaceutically acceptable carriers. the

A melanocortin receptor "agonist" means an endogenous substance, drug or compound, including a compound such as a peptide of the invention, which can interact with a melanocortin receptor and trigger the melanocortin receptor A pharmacological response (including, but not limited to, adenylate cyclase activation) that is characteristic of a hormone receptor. For the present invention, a melanocortin receptor agonist is preferred, which is an agonist at MCR-1. the

"α-MSH" means the peptide Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val- _NH2 (SEQ ID NO: 2) and its analogs and homologues substances, including but not limited to NDP-α-MSH.

"NDP-α-MSH" means the peptide Ac-Ser-Tyr-Ser-Nle-Glu-His-D-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH ₂ (SEQ ID NO: 3) and its Analogs and Homologues.

" _EC50 " means the molar concentration of an agonist, including a partial agonist, that produces 50% of the maximum possible response. As an example, a test compound at a concentration of 72 nM produces 50% of the maximal possible response in an MCR-1 cell expression system as determined by the cAMP assay, then the _EC50 of the test compound is 72 nM. Molar concentrations associated with _EC50 determinations are in nanomole per liter (nM) unless otherwise stated.

"Ki (nM)" denotes the equilibrium inhibitor dissociation constant representing the molar concentration of a competing compound that binds to one half of a receptor at equilibrium in the absence of radioligand or other competitor site binding. In general, the value of Ki is inversely related to the affinity of the compound for that receptor, so if the Ki is low, the affinity is high. Ki can be determined using the equation of Cheng and Prusoff (Cheng Y., Prusoff W.H. 22:3099-3108, 1973): in Biochem. Pharmacol. the

where "ligand" is the concentration of radioligand and _KD is the reciprocal of the affinity of the receptor for that radioligand that produces 50% receptor occupancy. Molarity relative to Ki determinations is in nM unless otherwise stated. Ki can use specific receptors (such as MCR-1, MCR-3, MCR-4 or MCR-5), specific species (such as human or murine) and specific ligands (such as α-MSH or NDP-α -MSH) expression.

"Inhibition"means the percent decrease or decrease in receptor binding in a competitive inhibition assay compared to a known standard. Therefore, "inhibition at 1 μM (NDP-α-MSH)" means, for example, under the assay conditions described below, by adding a defined amount of a test compound, such as a 1 μM test compound, the binding of NDP-α-MSH drop percentage. As an example, a test compound that does not inhibit NDP-α-MSH binding has 0% inhibition, while a test compound that completely inhibits NDP-α-MSH binding has 100% inhibition. Typically, as described below, a radioactive assay is used, e.g., in a competitive inhibition test using I ^- labeled NDP-α-MSH, or in a lanthanide chelate fluorometric assay, e.g., using Eu-NDP-α-MSH . However, other methods of testing for competitive inhibition are known, including the use of labels or labeling systems other than radioisotopes, and generally, any method known in the art for testing for competitive inhibition can be used in the present invention. Thus, it can be seen that "inhibition" is a measure to determine whether a test compound attenuates the binding of [alpha]-MSH to the melanocortin receptor.

"Binding affinity" means the ability of a compound or drug to bind to its biological target, expressed here as Ki (nM). the

In general, "functional activity" is a measure of a receptor signaling, or signaling associated with a receptor (such as a melanocortin receptor, especially MCR-1 or hMCR-1) when activated by a compound Measure of change. Melanocortin receptors initiate signaling through activation of heterotrimeric G proteins. On the one hand, melanocortin receptors signal through _GαS , _which uses adenylate cyclase to catalyze the generation of cAMP. Thus, determination of adenylate cyclase stimulation, eg, determination of maximal stimulation of adenylyl cyclase, is a measure of functional activity and is the primary measure exemplified herein. It should be understood, however, that alternative measures of functional activity may be used in the practice of the present invention and are expressly contemplated and included within the scope of the present invention. Thus, in one example, intracellular free calcium can be measured, such as Mountjoy, KG et al. "Melanocortin receptor-mediated mobilization of intracellular free calcium in HEK293 cells"cells)" (Physiol. Genomics 5:11-19 (2001)) or Kassack, MU et al. "Functional screening of G protein couples by measuring intracellular calcium with a fluorescent microplate reader (Functional screening of G protein-coupled receptors by measuring intracellular calcium with a fluorescence microplate reader)" (Biomol. Screening Journal (Biomol. Screening) 7: 233-246 (2002)) and using the report disclosed therein method. Activation can also be measured by measuring the generation of inositol triphosphate or diacylglycerol from phosphatidylinositol-4,5-bisphosphate, for example by using a radioactive assay. Yet another measure of functional activity is receptor internalization resulting from activation of regulatory pathways, e.g. using Nickolls, SA et al. "Functional selectivity of melanocortin 4 receptor peptide and non-peptide agonists: ligand-specific conformation (Functional selectivity of melanocortin 4 receptor peptide and nonpeptide agonists: evidence for ligand specific conformational states)" (J.Pharm.Exper.Therapeutics 313:1281-1288(2005)) method of disclosure. Yet another measure of functional activity is the exchange and exchange rate of nucleotides associated with activation of a G protein receptor, such as the exchange of GDP (guanosine diphosphate) to GTP (guanosine triphosphate) on the G protein alpha subunit. Exchange, which can be measured in many ways, including as in Manning, DR "Measures of efficacy using G proteins as endpoints: differential engagement of G proteins through single receptors)" (Mol.Pharmacol.) 62:451-452 (2002)), a radioactive assay using guanosine 5'-(γ-[ ^35S ]thio)-triphosphate . Various gene-based assays have been developed for measuring the activation of G-coupled proteins, such as Chen, W. et al. "A colorimetric assay from Measuring activation of Gs-and Gq-coupled signaling pathways)” (Analytical Biochemistry (Anal. Biochem.) 226:349-354 (1995)), Kent, TC et al. Development of a generic dual-reporter gene assay for screening G-protein-coupled receptors" (Biomol Screening 5:437-446 (2005)) or Kotarsky, K. et al. Human "Improved receptor gene assays used to identify ligands acting on orphan seven-transmembrane receptors" (Pharmacology and Toxicology & Toxicology) 93:249-258 (2003)). As in Hruby, VJ et al. "Cycle of Ac-Nle ⁴ -cyclo[Asp ⁵ ,D-Phe ⁷ ,Lys ¹⁰ ]α-melanostimulating hormone-(4-10)-NH ₂ with a large number of aromatic amino acids at position 7 Cyclic lactam α-melanocortin analogues of Ac-Nle ⁴ -cyclo[Asp ⁵ ,D- Phe ⁷ ,Lys ¹⁰ ]α-melanocyte-stimulating hormone-(4-10)-NH ₂ with bulky aromatic amino acids at position 7 shows high antagonist potency and selectivity at specific melanocortin receptors” (J.Med. The colorimetric assay of Chen et al. has been adapted for measuring melanocortin receptor activation as disclosed in Chem., 38:3454-3461 (1995). In general, functional activity can be measured by any method, including methods for determining activation and/or signaling of a G-coupled receptor, and further including methods that may be developed or reported in the future. Each of the above items and the methods disclosed therein are hereby incorporated by reference as if set forth in their entirety.

As used herein, the term "treat/treating/treatment" contemplates an effect of reducing the severity of a particular disease or disorder when a patient suffers from the disease or disorder. the

As used herein, the term "therapeutically effective amount" means the amount of a compound comprising a peptide of the invention that will elicit a biological or medical response in a mammal being treated by a physician or other clinician. the

As used herein, the term "prophylactically effective" or "preventive" means an amount of a compound comprising a peptide of the present invention that prevents or inhibits the suffering of a mammal having a physical condition or alleviates the suffering of the mammal, in Before a patient begins to suffer from a particular disease or disorder, a physician or other clinician endeavors to prevent, suppress, or alleviate the physical condition. the

"Circulatory shock" means a general medical condition in which the organs and/or tissues of the body of a subject, which may be a human or an animal, do not receive adequate blood flow. Circulatory shock includes conditions such as hypovolemic shock, cardiogenic shock, and vasodilatory shock. These circulatory conditions or dysfunctions can in turn have different causes, such as bacterial blood infection (septic shock or infection), severe allergic reaction (anaphylactic shock), trauma (traumatic shock), severe bleeding or blood loss (hemorrhagic shock ), abnormal opening of blood vessels due to neurological dysfunction (neurogenic shock), or endocrine-related (endocrine shock). Circulatory shock can further lead to ischemia and ischemic damage to organs, tissues, cells or parts of the body. Ischemia-reperfusion injury can occur when reperfusion, or restoration of blood flow, also results in damage to body organs, tissues or cells. the

"Inflammatory disease," sometimes called "inflammatory disorder," denotes a disease or disorder characterized in part by inflammatory mechanisms, such as specific T lymphocyte responses or antibody-antigen Recruitment of mediator chemicals, including but not limited to cytokines, including but not limited to increased NF-κB activity, increased TNF-α production, increased IL-1 production, and increased IL-6 production one or more of . the

2.0 Clinical indications and applications. the

The compositions and methods disclosed herein can be used in medical applications and animal husbandry or veterinary applications. Typically, these methods are used in humans, but can also be used in other mammals. The term "patient" refers to a mammalian individual, as used throughout this specification and claims. The primary application of the invention involves human patients, but the invention may also be used in laboratory animals, farm animals, zoo animals, wild animals, pets, sport animals or other animals. Clinical indications and specific applications include the following:

2.1 Inflammatory diseases, indications, conditions and syndromes. the

purpura）、银屑病性关节炎、反应性关节炎、血色素沉着病（haemochromatosis）、肝炎、韦格纳肉芽肿、血管炎综合征、莱姆病、家族性地中海热、反复发热性高免疫球蛋白D血症（hyperimmunoglobulinemia D with recurrent fever）、TNF受体相关的周期性综合征和炎性肠病，包括克罗恩病和溃疡性结肠炎。另一方面，所述炎性病症由一种疾病引起，所述疾病包括某种形式的炎性肠病，如克罗恩病、溃疡性结肠炎、胶原性结肠炎、淋巴细胞性结肠炎、缺血性结肠炎、改道性结肠炎、白塞综合征、感染性结肠炎和未定型结肠炎。另一方面，所述炎性病症由一种自身免疫性疾病引起，所述自身免疫性疾病包括但不限于全身综合征如系统性红斑狼疮、干燥综合征（ 

syndrome）、硬皮病、类风湿性关节炎和多肌炎，或者一种仅影响一个局部身体系统的综合征，如内分泌系统（1型糖尿病、桥本氏甲状腺炎、阿狄森病等）、皮肤系统（寻常天疱疮）、血液系统（自身免疫性溶血性贫血）或者神经系统（多发性硬化）。因此，除了上面讨论的一般综合征之外，自身免疫性疾病还包括这些疾病和病症，例如急性播散性脑脊髓炎、阿狄森病、强直性脊柱炎、抗磷脂抗体综合征、再生障碍性贫血、自身免疫性肝炎、自身免疫性卵巢炎、乳糜泻、克罗恩病、妊娠性类天疱疮、古德帕斯丘综合征（Goodpasture′s syndrome）、格雷夫斯病（Graves′disease）、格林-巴利综合征（Guillain-Barrésyndrome）、桥本氏病、特发性血小板减少 性紫癜、川崎病、红斑狼疮、混合性结缔组织病、多发性硬化、重症肌无力、眼阵挛-肌阵挛综合征（opsoclonus myoclonus syndrome）、视神经炎、自身免疫性甲状腺炎（Ord′s thyroiditis）、天疱疮、恶性贫血、原发性胆汁性肝硬化、莱特尔综合征、干燥综合征、大动脉炎（Takayasu′s arteritis）、颞动脉炎、自身免疫性溶血性贫血和韦格纳肉芽肿。  The peptides, compositions and methods of the invention are directed to treating inflammatory diseases and inflammatory conditions in a subject. There are many inflammatory diseases and inflammatory conditions that can be treated in this way. In one aspect, the inflammatory condition is caused by a disease comprising certain forms of arthritis including, but not limited to, osteoarthritis, rheumatoid arthritis, septic arthritis, gout and pseudogout, juvenile Idiopathic arthritis, Still's disease and ankylosing spondylitis, and arthritis secondary to other diseases, such as arthritis secondary to lupus erythematosus, Henoch-Schonlein purpura (Henoch-

purpura), psoriatic arthritis, reactive arthritis, haemochromatosis, hepatitis, Wegener's granulomatosis, vasculitis syndrome, Lyme disease, familial Mediterranean fever, recurrent febrile hyperimmune globulin Hyperimmunoglobulinemia D with recurrent fever, TNF receptor-associated periodic syndrome, and inflammatory bowel disease, including Crohn's disease and ulcerative colitis. In another aspect, the inflammatory condition is caused by a disease including certain forms of inflammatory bowel disease such as Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, Ischemic colitis, diversion colitis, Behcet's syndrome, infectious colitis, and indeterminate colitis. In another aspect, the inflammatory disorder is caused by an autoimmune disease including but not limited to systemic syndromes such as systemic lupus erythematosus, Sjogren's syndrome (

syndrome), scleroderma, rheumatoid arthritis, and polymyositis, or a syndrome affecting only one local body system, such as the endocrine system (type 1 diabetes, Hashimoto's thyroiditis, Addison's disease, etc.) , skin system (pemphigus vulgaris), blood system (autoimmune hemolytic anemia), or nervous system (multiple sclerosis). Thus, in addition to the general syndromes discussed above, autoimmune diseases include such diseases and conditions as acute disseminated encephalomyelitis, Addison's disease, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, autoimmune oophoritis, celiac disease, Crohn's disease, pemphigoid gestationis, Goodpasture's syndrome, Graves' disease disease), Guillain-Barré syndrome (Guillain-Barré syndrome), Hashimoto's disease, idiopathic thrombocytopenic purpura, Kawasaki disease, lupus erythematosus, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, eye array Opsoclonus myoclonus syndrome, optic neuritis, autoimmune thyroiditis (Ord's thyroiditis), pemphigus, pernicious anemia, primary biliary cirrhosis, Reiter's syndrome, Sjogren's syndrome Takayasu's arteritis, temporal arteritis, autoimmune hemolytic anemia, and Wegener's granulomatosis.

In another aspect, the inflammatory condition is caused by or associated with chronic obstructive pulmonary disease (COPD), also known as chronic obstructive respiratory disease, including, but not limited to, characterized by not fully reversible pathological airflow limitation in the airways Diseases such as chronic bronchitis, emphysema, pneumoconiosis, lung tumors and other lung disorders. Other inflammatory conditions include upper or lower airway diseases and disorders such as allergic asthma, non-allergic asthma, allergic rhinitis, vasomotor rhinitis, allergic conjunctivitis, non-allergic conjunctivitis, etc., as well as interactions with external toxins or substances Associated airway diseases such as various forms of pneumoconiosis (coal worker's pneumoconiosis, asbestosis, silicosis, bauxite fibrosis, beryllium poisoning or siderosis), cotton pneumoconiosis or hypersensitivity pneumoconiosis (farmer's or aviary's lung) . Other lung diseases involving an inflammatory condition include acute respiratory distress syndrome. The peptides and compositions of the invention are particularly useful in the treatment of conditions in which glucocorticoids are ineffective or insufficient to elicit the desired pharmacological response, such as COPD, asthma in smoking individuals and characterized wholly or in part by eosinophil accumulation in the lung, Neutrophil infiltration and activation, alveolar macrophage recruitment and activation, epithelial expression of IL-8, or other conditions with increased expression of TNF-α. For airway or pulmonary disorders, on the one hand, the peptides of the invention are delivered systemically; on the other hand, the peptides of the invention are delivered locally, eg by inhalation. the

In yet another aspect, the inflammatory disorder is caused by or associated with some form of transplant-associated disorder or syndrome, such as graft-versus-host disease, hyperacute rejection, acute rejection, or chronic rejection. Graft-versus-host disease is a common complication of allogeneic bone marrow transplantation but can arise in other transplants, particularly those in which T cells are present in the graft, whether introduced as contaminants or intentionally. Hyperacute, acute, or chronic rejection can occur in body organs such as the kidney, liver, pancreas, spleen, uterus, heart, or lungs, and in transplants of bone, stratum corneum, face, hand, penis, or skin. In one embodiment, a pharmaceutical composition comprising one or more peptides of the invention is provided prophylactically, e.g. immediately before, during or after transplantation of a body fluid, organ or part, to limit or prevent a transplantation Associated conditions or syndromes. In another embodiment, the body fluid, organ or part being transplanted is perfused with a solution of a pharmaceutical composition comprising one or more peptides of the invention. In yet another embodiment, one or more peptides of the invention are administered together with one or more other agents for transplant rejection, such as calcineurin inhibitors including cyclosporine or tacrolimus, mTOR inhibitors including sirolimus or everolimus, antiproliferative agents including azathioprine or mycophenolic acid, corticosteroids including prednisolone or hydrocortisone, antibodies such as monoclonal IL-2Rα receptor antibodies, basiliximab or daclizumab, or polyclonal anti-T cell antibodies such as antithymocyte globulin or antilymphocyte globulin. the

2.2 Fibrotic and sclerotic diseases, indications, conditions and syndromes. the

The present invention is peptides, compositions and methods directed to treating fibrotic and sclerotic diseases, indications, disorders and syndromes in a subject. There are many fibrotic and sclerotic diseases, indications, conditions and syndromes that can be so treated. Fibrotic and sclerotic diseases, indications, conditions and syndromes often include an inflammatory component and thus many can likewise be classified as an inflammatory disease or condition and are listed in section 2.1 above. In addition to including an inflammatory component, fibrotic and sclerotic diseases and disorders can also be idiopathic, toxic, genetic and/or pharmacologically induced disorders. Typically, fibrotic disorders are characterized by an overproduction of extracellular matrix, primarily type I collagen, which can lead to loss of organ function. It is believed, without wishing to be bound by theory, that agonism of MCR-1 can lead to inhibition of collagen synthesis induced by human dermal fibroblast transforming growth factor beta ₁ , thereby providing fibrotic and sclerotic diseases, indications, disorders and complexes. Therapeutic and/or prophylactic benefits of symptoms. Representative fibrotic and sclerotic diseases and disorders that may be so treated include, but are not limited to, localized scleroderma, systemic sclerosis, scleroderma skin graft-versus-host disease, idiopathic pulmonary fibrosis, bleomyces Toxin-induced pulmonary fibrosis, cyclosporine-induced nephropathy, liver cirrhosis, hypertrophic scars, keloids, etc.

2.3 Diseases associated with increased expression of cytokines and related diseases, indications, conditions and syndromes. the

During an inflammatory process, including one secondary to circulatory shock, ischemia, reperfusion injury, etc., the expression of various cytokines is increased. TNF-α is a pleiotropic cytokine mainly produced by macrophages and other cell types. Other cytokines that increase during an inflammatory process, including one secondary to circulatory shock, ischemia, reperfusion injury, etc., include IL-1 and IL-6. While cytokines such as TNF-α have beneficial effects in many situations, for example significantly elevated levels secondary to circulatory shock, ischemia, reperfusion injury, etc., can have pathological effects. On the one hand, hypoxia or ischemic tissue reperfusion, for example secondary to circulatory shock, results in an inflammatory response, including increased expression of cytokines. the

In one embodiment, the invention is directed to methods of using one or more peptides of the invention to reduce the production and expression of pro-inflammatory cytokines, including reducing pro-inflammatory cytokines secondary to circulatory shock, ischemia, reperfusion injury, and the like. Inflammatory cytokine production and expression. Decreased production and expression of pro-inflammatory cytokines (including but not limited to one or more of TNF-alpha, IL-1 and IL-6) following administration of a composition comprising one or more peptides of the invention Occurs immediately or within a short period of time, preferably within at least about 40 minutes after administration, more preferably within 1-20 minutes, more preferably within 1-15 minutes, most preferably within about 1-10 minutes. the

In a related embodiment, the invention is directed to methods of using one or more peptides of the invention to increase the production and expression of anti-inflammatory cytokines. Increased production and expression of anti-inflammatory cytokines (including but not limited to IL-10) occurs immediately or within a short period of administration of a composition comprising one or more peptides of the invention, preferably after administration At least within about 40 minutes, more preferably within 1-20 minutes, more preferably within 1-15 minutes, most preferably within about 1-10 minutes. the

2.4 Skin diseases, indications, conditions and syndromes. the

The peptides, compositions and methods of the invention are further directed to the treatment of skin and cosmetic diseases, indications, disorders and syndromes. In one aspect, the peptides and compositions of the invention are MCR-1 agonists, which stimulate melanocytes and related cells to increase melanin levels in the skin. Provides protection from ultraviolet radiation (UVR) and sunlight by increasing the level of melanin in the skin, including protection from skin phototoxicity and photosensitivity caused by UVR, the sun and light. the

In one aspect, the peptides, compositions and methods of the present invention can be used to prevent and/or treat dermal diseases, indications, conditions and syndromes, such as acne vulgaris (commonly known as acne), atopic dermatitis (commonly known as atopic dermatitis). atopic eczema or eczema), polymorphic light eruption, psoriasis, rosacea, seborrheic dermatitis, vitiligo, porphyria, porphyria cutanea tarda, erythropoietic protoporphyria, solar Urticaria, urticaria pigmentosa, or xeroderma pigmentosa. In another aspect, the peptides, compositions and methods of the invention can be used to prevent, inhibit or treat light-sensitive or photosensitive viral infections, such as herpes simplex virus (commonly known as cold sores and genital herpes depending on the site of infection), human milk Pillomavirus and varicella-zoster virus. In another aspect, the peptides, compositions and methods of the invention may be used to prevent, inhibit or treat skin cancer, including for precancerous conditions, and including for actinic keratoses, basal cell carcinoma, melanoma or squamous squamous cell carcinoma. In another aspect, the peptides, compositions and methods of the invention can be used to prevent or inhibit side effects of various therapies, including phototherapy, such as photodynamic therapy. In yet another aspect, the peptides, compositions and methods of the invention may be used to induce a tan, to reduce hair graying or for similar and related purposes related to increased melanin production. the

The peptides of the invention may be administered in any of a variety of ways, including direct application to the skin by oils, ointments, creams, gels, salves, etc., or by systemic administration, including by implants such as Dissolve the implant subcutaneously. the

2.5 Cytokine and/or growth factor responsive cancer

It has been reported that certain cancers such as mesothelioma are very sensitive to the growth-promoting effects of cytokines and growth factors and can be treated with peptides selective for MCR-1. "Autocrine inhibitory influences of α-melanocyte-stimulating hormone in malignant pleural mesothelioma" by Canania et al. (J. Leukoc. Biol. ) 75:253-259 (2004)). Cancers that may be so treated include pleural mesothelioma known to express mRHA directed against MCR-1 and receptor proteins, as well as other tumors that express MCR-1, including but not limited to adenocarcinomas such as lung adenocarcinoma. the

2.6 Eye diseases, indications, conditions and syndromes. the

There are numerous ocular diseases, indications, conditions and syndromes characterized by inflammation, including but not limited to increased cytokine production. An example is dry eye, an eye disease that affects approximately 10%-20% of the population. As people age, the disease progressively affects a larger proportion of the population, and the majority of these patients are women. Also, sometimes under certain circumstances, such as prolonged visual tasks (such as working on a computer), in a dry environment, almost everyone has experienced eye irritation, or as a symptom of dry eye syndrome and and/or signs, use of medications that cause eye dryness, etc. In individuals with dry eye, the protective tear layer that normally protects the ocular surface is compromised due to insufficient or unhealthy production of one or more tear components. This can lead to exposure of the ocular surface, ultimately promoting desiccation and damage to the surface cells. Signs and symptoms of dry eye include, but are not limited to, keratitis, staining of the conjunctiva and cornea, redness, blurred vision, decreased tear film break-up time, tear production, decreased tear volume and flow, increased conjunctival redness, Excessive debris, dry eyes, gritty eyes, burning eyes, foreign body sensation in eyes, excessive tearing, photophobia, eye irritation, refractive disturbances, eye sensitivity, and eye irritation. Patients may experience one or more of these symptoms. The excessive tearing response may seem counterintuitive, but it is a natural reflex response to the irritation and foreign body sensation that dry eye causes. Some patients may also experience itchy eyes due to a combination of ocular allergies and dry eye symptoms. the

There are many possible variables that can affect a patient's signs or symptoms of dry eye, including levels of circulating hormones, various autoimmune diseases (such as Sjogren's syndrome and systemic lupus erythematosus), eye surgery including excimer laser corneal Atomy surgery (PRK) or laser vision correction surgery (LASIK), many medications, environmental conditions, visual tasks such as computer use, eye strain, wearing contact lenses, and mechanical influences such as corneal sensitivity, partial eyelid closure, surface irregularities such as pterygium pterygium) and eyelid irregularities (eg, ptosis, entropion/ectropion, palpebral fissures). Low humidity environments, such as those that cause dehydration, can exacerbate or cause dry eye symptoms, such as sitting in a car with a defroster or living in a dry climate. Additionally, visual tasks can exacerbate symptoms. Tasks that can greatly affect symptoms include prolonged television viewing or computer use with a decreased blink rate. the

Uveitis is an eye disease involving inflammation of the middle layer of the eye, or uvea, and can also be understood to include any inflammatory process involving the interior of the eye. Uveitis includes anterior, intermediate, posterior and pan uveitis forms, with most cases of uveitis in an anterior location involving inflammation of the iris and anterior chamber. The condition may appear as a single episode and resolve with appropriate treatment or may have a relapsing or chronic nature. Symptoms include eye redness, injected conjunctiva, pain, and decreased vision. Signs include ciliary vasodilation, presence of cells and flares in the anterior chamber, and keratic deposits on the posterior surface of the cornea. Intermediate uveitis includes inflammation in the vitreous cavity and the presence of inflammatory cells, and posterior uveitis includes inflammation of the retina and choroid. Uveitis may be secondary to any of a number of diseases and disorders, including acute posterior multiple squamous pigment epitheliopathy, ankylosing spondylitis, Behcet's disease, birdshot retinochoroidopathy , brucellosis, herpes simplex, herpes zoster, inflammatory bowel disease, juvenile rheumatoid arthritis, Kawasaki disease, leptospirosis, Lyme disease, multiple sclerosis, psoriatic arthritis, Wright Syphilis syndrome, sarcoidosis, syphilis, systemic lupus erythematosus, toxocariasis, toxoplasmosis, tuberculosis, Vogt-Koyanagi-Harada syndrome, Whipple disease Or polyarteritis nodosa. the

In one embodiment, the present invention is directed to methods of treating any of the aforementioned ocular diseases, indications, disorders and syndromes using one or more peptides of the present invention. Such treatment may include treatment with eye drops, ointments, gels, lotions, implants, plugs or other means and methods and delivery of one or more peptides of the invention to the ocular surface. the

2.7 Ischemia and related diseases, indications, conditions and syndromes. the

Ischemia refers to any reduction or cessation of blood supply to any bodily organ, tissue, cell or part, especially where the reduction or cessation results or is likely to result in ischemic damage to the body organ, tissue, cell or part. "Ischemic episode" refers to any transient or permanent period of ischemia. Ischemia may be caused by any constriction or blockage of the vasculature, or may be caused by circulatory shock, such as hemorrhagic shock, hypovolemic shock, and the like. Reduced or insufficient blood flow results in decreased or insufficient oxygen to affected parts of the body and can also lead to an increase in chemical mediators of inflammatory disease such as various cytokines and other substances. During certain surgical procedures such as cardiac surgery and organ transplantation, blood flow is temporarily stopped and then restored (reperfused), resulting in ischemia-reperfusion injury. During a heart attack, the blood supply to the heart stops, also resulting in ischemia that can turn into an infarction. Current treatments to alleviate heart attacks require reperfusion of ischemic areas of the heart, such as with thrombolytic drugs or coronary angioplasty. the

The present invention is useful in preventing injury due to renal ischemia, including lung injury secondary to renal ischemia, preventing or limiting ischemic heart injury after myocardial infarction, preventing or limiting ischemic brain injury after cardiovascular injury, including but not It is limited to myocardial infarction, stroke and other aspects with special applications. Neuroprotection is provided by administering a composition of the present invention to a patient suffering from cerebral ischemia or stroke, especially concurrent hypotension. The invention has further particular application in preventing or limiting ischemic organ damage in organ transplantation, including transplantation of the heart, kidney, liver, lung, pancreas or small intestine. In one aspect, the pharmaceutical composition of the present invention can be used for perfusion of a transplanted organ, which can be performed before, during or after organ transplantation. the

In one embodiment, the invention is directed to methods of using one or more peptides of the invention to protect the heart, brain or other organs of a patient from damage due to ischemia. The protective effect against ischemia occurs immediately or within a short period of time after administration of a composition comprising one or more peptides of the present invention, preferably within at least about 40 minutes after administration, more preferably within 1-20 minutes. minutes, more preferably within 1-15 minutes, most preferably within about 1-10 minutes. the

Ischemia can also be caused by any of a variety of diseases or conditions, and in one embodiment, the invention is directed to a method of using one or more peptides of the invention to protect an organ of a patient from damage caused by ischemia, The ischemia is caused by a disease or condition. Such diseases or conditions may include, by way of example and without limitation, atherosclerotic diseases such as atheromata with thrombosis, embolism of blood vessels from the heart or any organ, vasospasm, Hypotension, hypotension due to systemic disease including infection or allergic reaction, or hypotension resulting from administration, ingestion, or other exposure to one or more toxic compounds or drugs. Ischemia can also be secondary ischemia, and in another embodiment, the invention is directed to a method of using one or more peptides of the invention to protect an organ of a patient from damage caused by secondary ischemia. This secondary ischemia can be secondary to a disease or condition such as diabetes, hyperlipidemia, hyperlipoproteinemia, dyslipidemia Buerger's disease (also known as thromboangiitis obliterans, Takayasu arteritis, arteritis temporalis, Kawasaki disease also known as lymph node syndrome, mucocutaneous lymph node disease, infantile polyarteritis, cardiovascular syphilis, and various connective tissue diseases and disorders. the

2.8 Ischemia-reperfusion injury and related diseases, indications, conditions and syndromes. the

Ischemia-reperfusion injury is an interruption of blood flow to body tissues, followed by an often sudden restoration of blood flow to the tissues. While restoration of blood flow after ischemia is essential to preserve functional tissue, reperfusion itself is known to be detrimental to tissue. Ischemia and reperfusion are known to be important causes of tissue necrosis. Several mechanisms appear to play a determinant role in generating the tissue damage associated with ischemia-reperfusion injury. the

Various methods of limiting reperfusion injury have been described, such as inducing hypothermia, controlling reperfusion, and ischemic preconditioning. Induced hypothermia is the induction of moderate hypothermia thought to inhibit many of the chemical reactions associated with reperfusion injury. Controlled reperfusion refers to controlling the initial phase of reperfusion by reperfusing tissue at low pressure with blood adjusted to be hypertonic, alkalotic, and substrate-rich. Ischemic preconditioning is the purposeful cause of short ischemic events to have a protective effect by slowing cellular metabolism during a longer ischemic event. While these treatments are useful in surgical situations (such as before or after planned heart surgery), they are not possible in emergency situations. the

The present invention is useful in preventing or limiting renal reperfusion injury, including lung injury secondary to renal reperfusion, preventing or limiting myocardial infarction reperfusion heart injury, preventing or limiting cardiovascular injury and reperfusion brain injury, including but not limited to myocardial Severity in terms of infarction, stroke, etc. has special application. The invention has further particular application in preventing or limiting reperfused organ injury in organ transplantation, including transplantation of the heart, kidney, liver, lung, pancreas or small intestine. In one aspect, the pharmaceutical composition of the present invention can be used for perfusion of a transplanted organ, which can be performed before, during or after organ transplantation. the

In one embodiment, the invention is directed to methods of using one or more peptides of the invention to protect the heart, brain or other organs of a patient from damage caused by ischemia-reperfusion injury, including injury caused by reperfusion or reperfusion Injury during perfusion. The protective effect against ischemia-reperfusion injury occurs immediately or within a short period of time after administration of a composition comprising one or more peptides of the present invention, preferably within at least about 40 minutes after administration, more preferably within Within 1-20 minutes, more preferably within 1-15 minutes, most preferably within about 1-10 minutes. the

2.9 Circulatory shock and related diseases, indications, conditions and syndromes. the

The peptides, compositions and methods of the invention can be used to treat circulatory shock in a subject. The compositions and methods provided herein can be used to treat stage I shock, stage II shock, or stage III shock. In a specific embodiment, the methods of the invention are used to treat the initial stages of shock characterized by insufficient cardiac output to meet the body's metabolic needs, but only so far, low enough to produce significant symptom. Patients may be anxious and alert, with increased breathing. the

"Phase I shock," sometimes called "compensatory shock" or "nonprogressive shock," refers to when the body senses a decrease in blood flow or perfusion and begins to activate one or more of a number of response mechanisms to restore A condition that occurs when vital body organs are perfused, or when blood flows directly to the most vital body organs. Stage I shock can be asymptomatic, but can also include, but is not limited to, symptoms of low blood flow or perfusion, rapid or rapid heart rate, shallow or irregular breathing, hypotension, hypertension, pallor, and cyanosis. the

"Stage II shock," sometimes called "decompensated shock" or "progressive shock," refers to a condition that occurs when the body's compensatory mechanisms begin to fail and organ perfusion cannot be normalized or maintained. Symptoms of stage II shock include, but are not limited to, confusion, anxiety, disorientation, and other mental disturbances indicating insufficient oxygen supply to the brain, chest pain, increased heart rate, oliguria, multiple organ dysfunction, and decreased blood pressure (hypotension) , shortness of breath, weakness, and dilated pupils. the

"Stage III shock," sometimes referred to as "irreversible shock," indicates a state of perfusion or reduced blood flow to such an extent that organs and tissues of the body are permanently affected. These symptoms include, but are not limited to, multiple organ failure, kidney failure, coma, blood pooling in the extremities, and death. the

The invention provides compositions for use and treatment or prevention of hemorrhagic shock in a patient comprising administering to a patient diagnosed with blood loss a composition comprising one or more peptides of the invention. Blood loss can, but need not be measured as a percentage of the subject's blood volume, eg, blood loss greater than about 15% of total blood volume or greater than 20%, 30%, 35%, 40%, or 50% of the subject's total volume. Alternatively, blood loss may, but need not, be measured as a drop in blood volume of any amount sufficient to cause hemorrhagic shock in a particular subject, for example, a loss of about 750 mL, 1000 mL, about 1500 mL, or about 2000 mL or more in a human subject. Blood loss can also be measured as a drop in systolic blood pressure, such as a drop in systolic blood pressure to approximately 20 mm Hg, 30 mm Hg, 40 mm Hg, 50 mm Hg, 60 mm Hg, 70 mm Hg below the subject's normal systolic blood pressure mmHg, 80 mmHg, 90 mmHg, or 100 mmHg or more than 100 mmHg. In specific embodiments, the subject is or has undergone a medical procedure such as, but not limited to, surgery, infusion, or childbirth. In other specific embodiments, the subject has suffered trauma, such as, but not limited to, resulting from a motor vehicle accident, an industrial injury, or a gunshot wound. the

In additional embodiments of the invention, the compositions and methods are used to treat cardiogenic shock, hypovolemic shock, and vasodilatory shock, each of which can be in any of the aforementioned stages of shock. In a specific embodiment of the invention, said method is used for the treatment of cardiogenic shock. In general, cardiogenic shock is low blood flow or perfusion caused by cardiac insufficiency, in which the heart does not pump enough blood. Causes may include any condition that interferes with ventricular filling or emptying, such as, but not limited to, embolism, ischemia, regurgitation, and valvular insufficiency. In another specific embodiment of the invention, said method is for the treatment of vasodilatory shock. Vasodilatory shock is caused by severe dilation of veins or arterioles, resulting in insufficient blood flow. Several known causes of vasodilatory shock include, but are not limited to, brain trauma, drug or poison toxicity, anaphylaxis, liver failure, bacteremia, and sepsis. In another more specific embodiment of the invention, said method is for the treatment of shock caused by sepsis or bacteremia. In an even more specific embodiment, these compositions and methods are used to treat stage I, II or III septic shock or bacteremic shock. In yet another embodiment, the compositions and methods of the invention are used to treat hypovolemic shock. In general, hypovolemic shock is a decrease in intravascular volume, which can be relative or absolute. Bleeding from conditions such as, but not limited to, ulcers, gastrointestinal injury, trauma, accidents, surgery, and aneurysms can lead to hypovolemic shock; however, loss of other body fluids can also lead to hypovolemic shock. For example, loss of renal fluid, intravascular fluid, or water or other peritoneal fluid can cause hypovolemic shock. In a particular embodiment of the invention, these compositions and methods comprising administering one or more peptides of the invention are used for the treatment of hypovolemic shock. In an even more specific embodiment, these compositions and methods are used to treat stage I, stage II or stage III hypovolemic shock. the

Circulatory shock includes hemorrhagic shock and can also be caused by controlled or uncontrolled bleeding from one or more internal organs or parts of blood vessels in a patient. Bleeding may be from any cause, including, by way of example, from a ruptured aneurysm, dissected aorta, ulcer, trauma, or other gastrointestinal bleeding. In some cases, patients present with signs of circulatory shock or hypovolemia, which can include hypotension, but the source of internal bleeding is unknown. the

In one embodiment, the invention is directed to a method of using one or more peptides of the invention to protect the heart, brain or other organs of a patient from damage caused by circulatory shock. The protective effect against circulatory shock occurs immediately or within a short period of time after administration of a composition comprising one or more peptides of the present invention, preferably within at least about 40 minutes after administration, more preferably within 1- Within 20 minutes, more preferably within 1-15 minutes, most preferably within about 1-10 minutes. the

2.10 Targeted imaging and cytotoxic therapy for melanoma and other indications. the

For example, the peptides, compositions and methods of the invention are useful for imaging melanoma and other cancers characterized in part by relatively high expression of MCR-1 by using a radionuclide in combination with a peptide of the invention for diagnostic imaging or disease or condition. For diagnostic imaging, typically, a peptide of the invention is conjugated to a radionuclide using a linker, such as a cross-linking agent, that couples the peptide of the invention and a radionuclide. Preferably, the radionuclide is a gamma emitter that can be imaged using a gamma detector or camera such as single photon emission computed tomography, or a gamma emitter that can be imaged using positron emission Positron emitters for tomography imaging. Among others, gamma emitters that can be used in this way include ^99m Tc, ¹¹¹ In, ¹²³ I, and ⁶⁷ Ga. Positron emitters that can be used in this way ^include11C , ^13N , ^{15O and18F} .

In a related aspect, the peptides, compositions and methods of the invention may be used in a peptide characterized in part by a relatively high MCR, e.g. by using in combination a chemotherapeutic (including toxin) or radiotherapeutic agent, in combination with a peptide of the invention Cytotoxic therapy of -1 expressing melanoma, other cancers or diseases or conditions. Chemotherapeutic agents include any antineoplastic drug or chemical such as alkylating agents, antimetabolites, anthracyclines, plant alkaloids, topoisomerase inhibitors, and other antineoplastic agents. Non-limiting examples of alkylating agents include cisplatin, carboplatin, oxaliplatin, mechlorethamine, cyclophosphamide, chlorambucil, and ifosfamide; examples of antimetabolites include azathioprine and mercaptopurine ; Examples of anthracyclines include daunorubicin, doxorubicin, epirubicin, idarubicin, valrubicin, and mitoxantrone; examples of plant alkaloids include vinca alkaloids such as Vinca Neosine, vinblastine, vinorelbine and vindesine and taxanes such as paclitaxel and docetaxel; examples of topoisomerase inhibitors include camptothecins such as irinotecan and topotecan and type II topoisomerase inhibitors Isomerases such as amsacrine, etoposide, etoposide phosphate and teniposide. However, any substance suitable for use in targeted cytotoxic therapy can be used as such. Among others, non-limiting examples of radiotherapeutic agents that can be used in this way include ¹³¹ I, ¹²⁵ I, ²¹¹ At, ¹⁸⁶ Re, ¹⁸⁸ Re, ⁹⁰ Y, ¹⁵³ Sm, ²¹² Bi, and ³² P.

Where, for example, using ¹¹ C, ¹³ N, ¹⁵ O instead of non-radioactive isotopes, diagnostic imaging or cytotoxic therapy substances can be combined with a peptide of the invention; Peptides are directly linked; or indirectly linked to a peptide of the invention, for example, using a linker or chelating unit. Linking units are well known in the art and include, but are not limited to, chemically linked conjugates comprising at least one disulfide, thioether, or covalent bond between free reactive groups. Of these, representative crosslinking and binding reagents are disclosed in US Patent Nos. 7,169,603, 7,820,164, and 5,443,816, and US Publication No. 2009/0297444, incorporated herein by reference.

3.0 Combination therapy for certain indications. the

These peptides, compositions and methods of the invention may be used to treat any of the aforementioned diseases, indications, disorders or syndromes, or any MCR-1 mediated or responsive diseases, indications, conditions or syndromes. Such conjoint administration may be by means of a single dosage form comprising a peptide of the invention and one or more other pharmaceutically active compounds, such single dosage form including a tablet, capsule, spray, inhalation powder, injection, etc. Alternatively, co-administration may be by means of administering two different dosage forms, one containing one of the peptides of the invention and the other containing the other pharmaceutically active compound. In this case, the dosage forms may be the same or different. The term "coadminister" indicates that in combination therapy each of at least two compounds is administered within a time frame in which the corresponding periods of biological activity or effect overlap. Thus, the term includes sequential as well as simultaneous administration of compounds, one of which is one or more peptides of the invention. If more than one compound is administered simultaneously, the route of administration of the two or more compounds need not be the same. Without intending to limit combination therapies, some combination therapies that may be employed are exemplified below. the

3.1 Combination therapy with anti-inflammatory agents. the

或西乐葆 

）、细胞毒性T淋巴细胞相关抗原4免疫球蛋白（CTLA4-Ig）激动剂/拮抗剂、CD40配体拮抗剂、次黄嘌呤单磷酸脱氢酶（IMPDH）抑制剂如霉酚酸酯（CellCept ）、整联蛋白拮抗剂、α-4β-7整联蛋白拮抗剂、细胞粘附抑制剂、干扰素-γ拮抗剂、细胞间粘附分子-1（ICAM-1）、前列腺素合成抑制剂、布地奈德、氯法齐明、p38丝裂原活化蛋白激酶抑制剂、蛋白酪氨酸激酶（PTK）抑制剂、IκB激酶（IKK）抑制剂、用于治疗肠易激综合征的疗法（例如Zelmac 和Maxi-K 

开放剂如美国专利号6,184,231中披露的那些）或者其他核因子κB（NF-κB）抑制剂，如美国专利号4,200,750中披露的皮质类固醇、钙磷酸蛋白（calphostin）、 CSAID、4-取代咪唑并[1，2-A]喹喔啉；白细胞介素-10、水杨酸盐类、一氧化氮和其他免疫抑制剂；以及核转位抑制剂，如脱氧精胍菌素（DSG）。  1. For the treatment of diseases, indications, disorders and syndromes associated with inflammation, the peptides of the invention may be used in combination therapy, including by means of simultaneous administration with one or more anti-inflammatory agents. One class of anti-inflammatory agents are glucocorticoids, including but not limited to cortisone, including cortisone acetate, hydrocortisone, prednisone, prednisolone, methylprednisolone, dexamethasone, Tamethasone, triamcinolone, beclomethasone, prednisone, fludrocortisone acetate, deoxycorticosterone acetate, and aldosterone. Other anti-inflammatory agents that can be used in combination therapy include aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and naproxen, TNF-alpha inhibitors such as tenidap and Rapamycin or its derivatives) or TNF-α antagonists (eg, infliximab, OR1384), cyclooxygenase inhibitors (ie, COX-1 and/or COX-2 inhibitors such as naproxen

or Celebrex

), cytotoxic T lymphocyte-associated antigen 4 immunoglobulin (CTLA4-Ig) agonists/antagonists, CD40 ligand antagonists, hypoxanthine monophosphate dehydrogenase (IMPDH) inhibitors such as mycophenolate mofetil (CellCept ), integrin antagonists, alpha-4beta-7 integrin antagonists, cell adhesion inhibitors, interferon-gamma antagonists, intercellular adhesion molecule-1 (ICAM-1), prostaglandin synthesis inhibitors , budesonide, clofazimine, p38 mitogen-activated protein kinase inhibitors, protein tyrosine kinase (PTK) inhibitors, IκB kinase (IKK) inhibitors, therapy for irritable bowel syndrome ( e.g. Zelmac and Maxi-K

Openers such as those disclosed in U.S. Patent No. 6,184,231) or other nuclear factor kappa B (NF-κB) inhibitors such as corticosteroids, calphostin, CSAIDs, 4-substituted imidazolos disclosed in U.S. Patent No. 4,200,750 [1,2-A]quinoxaline; interleukin-10, salicylates, nitric oxide, and other immunosuppressants; and nuclear translocation inhibitors such as deoxyspergualin (DSG).

3.2 Combination therapy with phosphodiesterase inhibitors. the

For certain applications and indications, it is desirable to increase the generation and maintenance of adenosine-3',5'-cyclic monophosphate (cAMP), a nucleotide messenger associated with inflammatory cell activity . The peptides of the present invention increase intracellular levels of cAMP and can be administered simultaneously with compounds or substances that inhibit the degradation of cAMP. cAMP is hydrolyzed to an inactive form by phosphodiesterase (PDE); thus, a compound or substance that inhibits PDE can result in the maintenance and/or increase of available cAMP. A class of compounds known as PDE inhibitors has been extensively studied for the treatment of inflammatory diseases such as asthma, chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome. Preferably a PDE type 1, type 2, type 3, type 4, type 7, type 8, type 10 or type 11 inhibitor; in one aspect, this includes a cAMP-PDE inhibitor that is a selective PDE type 4 inhibitor or Inhibitors that are selective for one specific type of PDE 4 isoenzyme, such as rolipram, cilomilast, ibudilast, and piramilast. In general, the methods and compositions of the invention may involve the use of one or more of the cAMP-PDE inhibitors described in one or more of the following U.S. patents or patent applications, each of which is incorporated herein by reference : U.S. Patent Application No. 20090221664 "Pharmaceutical Compositions of Muscarinic Receptor Antagonists"; U.S. Patent Application No. 20090054382 "Compositions of Phosphodiesterase Type IV Inhibitors" Phosphodiesterase Type IV Inhibitors)”; U.S. Patent Application No. 20090017036 “Pharmaceutical Compositions for Treatment of Respiratory and Gastrointestinal Disorders”; U.S. Patent Application No. PDE Type IV Inhibitors and Optically Pure Glycopyrrolate Salts (Medicaments for Inhalation Comprising PDE IV Inhibitors and Enantiomerically Pure Glycopyrrolate Salts)"; US Patent Application No. 20080085858 "Pharmaceutical Composition (Pharmaceutical Composition)"; US Patent Application No. 20080045718 "Process and intermediates for the synthesis of 2-(quinolin-5-yl)-4,5 disubstituted azole derivatives and intermediates (Process and intermediates for the synthesis of 2-(quinolin-5-yl)-4 ,5 dissubstituted-azole derivatives)”; U.S. Patent Application No. 20070287689 “Therapeutic and/or Preventive Agents for Chronic Skin Diseases”; U.S. Patent Application No. 20060239927 “Use "Drug for airway administration"; "Chemical compounds with dual ac tivity, processes for their preparation and pharmaceutical compositions)”; U.S. Patent No. 7,459,451 “Pyrazolopyridine derivatives”; U.S. Patent No. 7,317,009 “Pyrrolopyridazine derivatives”; U.S. Patent "Benzoylpyridazines" of US Patent No. 7,312,328; "Pyrrolopyridazine derivatives" of US Patent No. 7,153,854; "PDE IV inhibitors" of US Patent No. 7,115,623; Patent No. 6,924,292 "Furoisoquinoline derivatives, process for producing the same and use thereof"; U.S. Patent No. 6,872,382 "Selective PDE IV inhibitors for the treatment of dry eye Uses (Use of selective PDE IV inhibitors to treat dry eye disorders)"; US Patent No. 6,765,095 "2,3-disubstituted pyridine derivatives, their preparation methods, pharmaceutical compositions containing them, and intermediates therefor ( 2,3-disstituted pyridine derivative, process for the preparation thereof, pharmaceutical composition containing the same, and intermediate therefor)”; U.S. Patent No. 6,740,662 of “Naphthyridine derivatives”; U.S. Patent No. 6,683,186 of “2, 3-Disubstituted pyridine derivatives, process for their preparation, pharmaceutical compositions containing them, and intermediates therefor ";beautiful "PDE IV inhibiting pyridine derivatives" of US Patent No. 6,656,959; "1,8-naphthyridin-2(1H)-one derivatives (1,8-naphthyridin-2 (1H)-one derivatives)”; U.S. Patent No. 6,555,557 “2,3-disubstituted pyridine derivatives, methods for their preparation, pharmaceutical compositions containing 2,3-disubstituted pyridine derivatives, and Intermediates (2,3-disstituted pyridine derivatives, process for the preparation thereof, drug compositions containing the same and intermediates for the preparation)"; U.S. Patent No. 6,440,979 "Aryl isoguanines (Aryl isoguanines)"; U.S. Patent No. "PDE IV inhibiting amides, compositions and methods of treatment" of 6,436,965; "Tricyclic nitrogen heterocycles as PDE IV inhibitors" of U.S. Patent No. 6,417,190 IV inhibitors)”; US Patent No. 6,413,975 “Purine derivatives having phosphodiesterase IV inhibition activity”; US Patent No. 6,403,805 “1,3-dihydro-1-( phenylalkyl)-2H-imidazol-2-one derivatives (1,3-dihydro-1-(phenylalkyl)-2H-imidazol-2-one derivatives)”; U.S. Patent No. 6,372,770 “Benzoxazole ( Benzoxazoles)”; U.S. Patent No. 6,365,606 “6,5-fused aromatic ring systems having enhanced phosphodiesterase IV inhibitory activity”; U.S. Patent No. 6,310,205 The "hypoxanthination "Hypoxathine compounds"; U.S. Patent No. 6,306,583 "Human brain phosphodiesterase"; U.S. Patent No. 6,268,373 "Trisubstituted thioxanthines"; U.S. Patent No. 6,248,769 "Phenyl-triazole compounds for PDE-IV inhibition"; US Patent No. 6,248,768 "Benzimidazole derivatives and pharmaceutically acceptable salts thereof" and pharmaceutically acceptable salts thereof)”; “3-(arylalkyl) xanthines” of U.S. Patent No. 6,248,746; “Substituted indazole derivatives and related Compounds (Substituted indazole derivatives and related compounds)”; U.S. Patent No. 6,211,203 for “Benzofuran-4-carboxamides”; U.S. Patent No. 6,200,993 for “Hetero-substituted pyridine derivatives as PDE4 inhibitors (Heterosubstituted pyridine derivatives as PDE4 inhibitors)"; U.S. Patent No. 6,191,138 "Phenanthridines"; U.S. Patent No. 6,180,650 "Heterosubstituted pyridine derivatives as PDE4 inhibitors (Heterosubstituted pyridine derivatives as PDE4 inhibitors)"; "Naphthyridine derivatives" of Patent No. 6,136,821; "Substituted dihydrobenzofuran-based phosphodiesterase 4 Inhibitors for use in the treatment of respiratory disorders" of U.S. Patent No. 6,054,475 useful for treating airway disorders); "(2,3-dihydrobenzofuranyl)- Thiazoles as phosphodiesterase inhibitors ((2,3-dihydrobenzofuranyl)-thiazoles as phosphodiesterase inhibitors); U.S. Patent No. 6,011,037 "Thiazole derivatives with phosphodiesterase-inhibiting action "; U.S. Patent No. 5,972,927 "Diazepinoindoles as phosphodiesterase 4 inhibitors"; U.S. Patent No. 5,919,801 "N-substituted piperidines as PDE4 inhibitors (N- substituted piperidines as PDE4 inhibitors)”; US Patent No. 6,204,275 “PDE IV Inhibiting Compounds, Compositions and Methods of Treatment (PDE IV Inhibiting compounds, compositions and methods of treatment)”; Anti-inflammatory and anti-asthma treatment with reduced side effects”; U.S. Patent No. 6,103,749 “Aryl imidazole compounds having phosphodiesterase IV activity”; U.S. Patent "Compounds containing phenyl linked to aryl or heteroaryl by an aliphatic or heteroatom containing linking group" of No. 6,096,768; USA Patent No. 6,075,016 for "6,5-fused aromatic ring systems having enhanced phosphodiesterase IV inhibitory activity"; U.S. Patent No. 6,040,447 for "Having PDE IV inhibitory activity of purine compound and synthetic method (Pu rine compounds having PDE IV inhibitory activity and methods of synthesis)”; U.S. Patent No. 6,034,089 “Aryl thiophene derivatives as PDE IV inhibitors”; U.S. Patent No. 6,020,33 “Aryl "Aryl furan derivatives as PDE IV inhibitors"; U.S. Patent No. 5,935,978 "Containing a phenyl group linked to an aryl or heteroaryl group through an aliphatic or heteroatom-containing linking group Compounds containing phenyl linked to aryl or heteroaryl by an aliphatic or heteroatom containing linking group”; U.S. Patent No. 5,935,977, “Substituted vinyl pyridine derivative and drugs containing same” ; Compounds containing phenyl linked to aryl or heteroaryl by an aliphatic or heteroatom containing linking group of U.S. Patent No. 5,840,724 "; U.S. Patent No. 5,710,170 "Tri-arylethane derivatives as PDE IV inhibitors"; U.S. Patent No. 5,710,160 "Diphenylpyridylethane derivatives as PDE IV Diphenyl pyridyl ethane derivatives as PDE IV inhibitors"; U.S. Patent No. 5,698,711 "Compounds containing phenyl linked to aryl or heteroaryl through an aliphatic or heteroatom-containing linking group to aryl or heteroaryl by an aliphatic or heteroatom cont aining linking group)”; U.S. Patent No. 5,691,376 for “Substituted biphenyl derivatives”; U.S. Patent No. 5,679,696 for “containing an "Compounds containing phenyl linked to aryl or heteroaryl by an aliphatic or heteroatom containing linking group"; U.S. Patent No. 5,665,737 "Substituted benzoxazoles"; U.S. Patent No. 5,650,444 "Substituted biphenyl derivatives"; "Naphthylalkylamines" of U.S. Patent No. 5,616,614; "1-alkoxy-2-(alkoxy or Cycloalkoxy)-4-(cycloalkoxy-alkyl or cycloalkoxyalkenyl)benzene as an inhibitor of cyclic AMP phosphodiesterase and tumor necrosis factor (1-Alkoxy-2-(alkoxy or cycloalkoxy)-4 -(cyclothio-alkyl or cyclothioalkenyl)benzenes as inhibitors of cyclic AMP phosphodiesterase and tumor necrosis factor); U.S. Patent No. 5,502,072 "Substituted oxindoles"; U.S. Patent No. 1,6-Naphthyri-dine-5-ones (8-phenyl-1,6-naphthyri-dine-5-ones)”; U.S. Patent No. 5,459,151 “N-acyl-substituted phenylpiperidines as bronchodilators and inflammatory agents (N-acyl substituted phenyl piperidines as bronchodilators and anti-inflammatory agents)”; U.S. Patent No. 5,393,788 “Phenylalkyl oxamides”; U.S. Patent No. 5,356,923 “1-hydroxy-4(3 -cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone and its antihypertensive use (1-hydroxy-4(3-cy clopentyloxy-4-methoxyphenyl)-2-pyrrolidone and anti-hypertensive use thereof”; U.S. Patent No. 5,250,700 “Phenyl pyrazolidinones as bronchodilators and anti-inflammatory agents "; U.S. Patent No. 5,191,084 "Phenyl pyrazolidinones as bronchodilators and anti-inflammatory agents"; U.S. Patent No. 5,124,455 "Oxime carbamates and oxime carbonates as "Oxime carbamates and oxime carbonates as bronchodilators and anti-inflammatory agents"; U.S. Patent No. 6,180,791 "Synthesis of 8-substituted xanthines"; U.S. Patent No. 6,057,369 "Substituted (aryl, heteroaryl, arylmethyl or heteroarylmethyl) hydroxamic acid compounds" of U.S. Patent No. 5,541,219 1-Alkoxy-2-(alkoxy or cycloalkoxy)-4-(cyclomercaptoalkyl or cyclomercaptoalkenyl)benzene as an inhibitor of cyclic AMP phosphodiesterase and tumor necrosis factor (1 -Alkoxy-2-(alkoxy or cycloalkoxy)-4-(cyclothioalkyl or cyclothioalkenyl)benzenes as inhibitors of cyclic AMP phosphodiesterase and tumor necrosis factor)"; U.S. Patent No. 5,362,915 "Phenyl-substituted Cycloalkenyl compounds (Phenyl substituted cycloalkenyl compounds useful as PDE IV inhibitors)”; U.S. Patent No. 6,040,329 “Substituting ted indazole analogs)”; U.S. Patent No. 5,958,953, “Substituted indazole derivatives”; U.S. Patent No. 6,090,817, “Phenylpyridine derivatives useful as phosphodiesterase inhibitors as phosphodiesterase inhibitors)”; U.S. Patent No. 5,922,740 “Heterocyclylcarbonyl substituted benzofuranylureas”; U.S. Patent No. 5,866,571 “9-substituted 2-2-n-alkoxyphenyl )-purin-6-ones (9-substituted 2-2-n-alkoxyphenyl)-purin-6-ones-)”; U.S. Patent No. 5,861,404 “2,9-disubstituted purin-6-ones (2, 9-dissubstituted purin-6-ones)”; U.S. Patent No. 5,861,39 “Purin-6-one derivatives”; U.S. Patent No. 5,721,238 “2,8-disubstituted quinone Pyrido 3,2-pyrazinones with anti-asthmatic activity and methods for their preparation (Pyrido 3,2-Pyrazinones with Anti-asthmatic action and Processes for their Manufacturing)”; U.S. Patent No. 5,596,013 for “Dihydro pyrazolopyrroles.” the

3.3 Combination therapy in ocular indications. the

-Allergan）。也有可能的是，同时给予包括给予除了一种本发明的肽之外的一种或多种另外的化合物，例如单独给予一种眼科剂型，该眼科剂型包含一种人工泪液成分、一种局部皮质类固醇、一种非甾体抗炎药、一种钙调磷酸酶抑制剂如环孢素-A或者任何前述化合物的一种组合。  For ocular indications, an ophthalmic dosage form may contain, in addition to one or more peptides of the invention, one or more active ingredients, such as artificial tear ingredients, topical corticosteroids, nonsteroidal anti-inflammatory drugs, or calcium Phosphatine inhibitors such as cyclosporine-A (Restasis

-Allergan). It is also possible that simultaneous administration comprises the administration of one or more additional compounds in addition to a peptide of the invention, for example the sole administration of an ophthalmic dosage form comprising an artificial tear composition, a topical cortical Steroids, a non-steroidal anti-inflammatory drug, a calcineurin inhibitor such as cyclosporine-A, or a combination of any of the foregoing.

Combination eye drops may be employed, specifically including solutions containing more than one active pharmaceutical ingredient. In one aspect, a non-steroidal anti-inflammatory drug (NSAID) and a peptide of the invention may be used in combination. NSAIDs suitable for use in combination eye drops include agents that inhibit cyclooxygenase (COX)-1 and/or -2 enzymes, their esters and pharmaceutically acceptable salts thereof, including but not limited to propionic acid compounds such as naphthalene Proxan, flurbiprofen, oxaprozin, ibuprofen, ketoprofen, fenoprofen; ketorolac tromethamine; acetic acid derivatives such as sulindac, indomethacin, and etodolac ; phenylacetic acids such as diclofenac, bromfenac, and suprofen; aryl acetate prodrugs such as nepafenac and amfenac; Magnesium base; para-aminophenol derivatives such as acetaminophen; naphthylalkanones such as nabumetone; enolic acid derivatives such as piroxicam and meloxicam; fenamates such as mefenamic acid , meclofenamate, and flufenamic acid; pyrrole acetic acid, such as tolmetin; and pyrazolones, such as benzobutazone; and COX-2 selective inhibitors, such as celecoxib, valdecoxib, parecoxib Etoricoxib, etoricoxib, and lumiracoxib. The eye drops may additionally contain other active ingredients including, but not limited to, vasoconstrictors, antiallergic agents, anti-infectives, steroids, anesthetics, anti-inflammatory drugs, analgesics, dry eye therapeutics (such as secretagogues, mucomimetics, polymers, lipids, antioxidants), etc., or administered together (simultaneously or sequentially) with pharmaceutical compositions containing other active ingredients, including but not limited to vasoconstrictors, Antiallergic agents, anti-infectives, steroids, anesthetics, anti-inflammatory drugs, analgesics, dry eye treatment agents (such as secretagogues, mucosal mimics, polymers, lipids, antioxidants), etc. the

3.4 Combination therapy in shock-related indications. the

The method of treating or preventing circulatory shock of the present invention also involves simultaneously administering to a subject one or more substances in addition to one or more peptides of the present invention. For example, one or more peptides of the invention may be administered concomitantly with androstenediol, androstenediol or derivatives thereof, various vasopressin agonists, or other pharmaceutically active substances such as catecholamines or other alpha adrenergic agonists, alpha ₂ adrenergic agonists, beta adrenergic agonists or beta ₂ adrenergic agonists including but not limited to epinephrine, norepinephrine, dopamine, isoproterenol , vasopressin, and dobutamine. Alternatively, one or more peptides of the invention may be administered concurrently with fluids or other substances capable of alleviating, alleviating, preventing or eliminating symptoms in a subject suffering from hypovolemic shock, vascular Dilated shock or cardiogenic shock, exhibiting symptoms of or being at risk of developing these shocks. The type of fluid that can be administered concomitantly with one or more peptides of the invention should be specific to the circumstances surrounding the particular subject suffering from, exhibiting symptoms of, or at risk of developing shock. For example, fluids that can be administered simultaneously with one or more peptides of the invention include, but are not limited to, saline solutions—such as sodium chloride and sodium bicarbonate—as well as whole blood, artificial blood substitutes, plasma, serum, serum albumin, and colloidal solution. Colloidal solutions include, but are not limited to, solutions containing hydroxyethyl starch, albumin, or plasma. In a specific embodiment of the invention, one or more of the peptides of the invention are mixed with one or more of the fluids in the patient, such as saline solution, colloid solution, whole blood, artificial blood substitutes, plasma or serum. While administered, the patient suffers from or exhibits symptoms of a hypovolemic shock such as hemorrhagic shock.

A specific embodiment of the simultaneous administration method of the present invention includes a method of performing an infusion in a subject comprising administering blood or an artificial blood substitute comprising one or more peptides of the present invention to a subject. The blood used in the transfusion method can be whole blood, an artificial blood substitute, or any fraction of whole blood, such as plasma, serum or red blood cells. the

4.0 Administration method and usage. the

Methods of administration and uses vary according to the characteristics of the specific peptide of the invention, the disease, indication, condition or syndrome to be treated, and other factors known in the art. In general, any method of administration and use known in the art or later developed can be employed with the peptides of the present invention. Without limiting the foregoing, the following methods of administration and uses have particular application. the

4.1 Inhalation use. the

In one aspect, a composition comprising one or more peptides of the invention is formulated for respiratory administration, such as in the form of an aerosol or solution in a nebulizer, or an ultrafine powder alone or in combination with a or inert carriers or additional active pharmaceutical ingredients for insufflation or inhalation (such as topical administration to the lungs or/respiratory tracts), and in the form of a solution, a suspension, an aerosol or a dry powder formulation . See generally, "Carrier-based strategies for targeting protein and peptide drugs to the lungs" by Cryan, S.-A. (AAPS Journal) 7: E20-41 (2005)). In general, the peptides of the invention may be used in the devices, formulations, compositions and implements described in one or more of the following U.S. patents or patent applications, each of which is incorporated herein by reference: U.S. Patent Application No. 20090241949 "Dry powder inhalation system"; US Patent Application No. 20080066741 "Methods and systems of delivering medication via inhalation"; US Patent Application No. 20070298116 "Contains Amorphous, spray-dried powders having a reduced moisture content and a high long term stability”; U.S. Patent Application No. 20070140976 “Aqueous inhalation pharmaceutical composition composition)”; U.S. Patent Application No. 20060054166 for “Inhalation nebulizer”; U.S. Patent Application No. 20050211244 for “Dry powder preparations”; U.S. Patent Application No. 20050123509 for “adjusting charge density to improve spray drying "Modulating charge density to produce improvements in the characteristics of spray-dried proteins"; US Patent Application No. 20040241232 "Dry powder medicament formulations"; US Patent No. 7,582,284 "Particulate matter (Particulate matter) materials)”; U.S. Patent No. 7,481,212 “Increased dosage metered dose inhaler”; U.S. Patent No. 7,387,794 “Powder Agglomerates (Preparation of powder agglomerate)”; U.S. Patent No. 7,258,873 "Preservation of bioactive materials by spray drying )”; U.S. Patent No. 7,186,401 “Dry powder for inhalation”; U.S. Patent No. 7,143,764 “Inhalation device (Inhalation device)”; U.S. Patent No. 7,022,311 “Powder inhalation preparation and its production method (Powdery inhalational preparations and process for producing the same)"; US Patent No. 6,962,151 "Inhalation Nebulizer"; US Patent No. 6,907,880 "Inhalation device (Inhalation device)"; US Patent No. 6,881,398 "Therapeutic Dry Powder Preparation (Therapeutic dry powder preparation)”; US Patent No. 6,698,425 “Powder inhaler”; US Patent No. 6,655,380 “Inhalation device (Inhalation device)”; US Patent No. 6,645,466 “Dry powder for inhalation (Dry powder for inhalation)”; U.S. Patent No. 6,632,456, “Compositions for inhalation”; U.S. Patent No. 6,610,272, “Medicinal aerosol formulation”; U.S. Patent No. 6,596,261 "Method of administering a medicinal aerosol formulation"; "Medicinal aerosol formulation" of U.S. Patent No. 6,585,957; "Medicinal aerosol formulation" of U.S. Patent No. 6,582,729 "Powered pharmaceutical formulations having improved dispersibility"; U.S. Patent No. 6,572,893 "Systems and processes for spray drying hydrophobic drugs with hydrophilic excipients with hydrophilic excipients)”; U.S. Patent No. 6,551,578 “Modulated Release Particles for Aerosol Delivery (Modulated release particles for aerosol delivery)"; U.S. Patent No. 6,520,179 "Inhalation device (Inhalation device)"; U.S. Patent No. 6,518,239 "Dry powder compositions having improved dispersibility"; U.S. Patent No. 6,503,481 "Compositions for aerosolization and inhalation"; US Patent No. 6,358,530 "Powdered pharmaceutical formulations having improved dispersibility"; US Patent No. 6,325,061 "Inhalation device (Inhalation device)" of U.S. Patent No. 6,257,232; "Powdered pharmaceutical formulations having improved dispersibility" of U.S. Patent No. 6,187,344; US Patent No. 6,116,237 "Methods of dry powder inhalation"; US Patent No. 5,934,272 "Device and method of creating aerosolized mist of respiratory drug"; US Patent No. 5,558,085 "Intrapulmonary delivery of peptide drugs." the

Thus, the composition may be a dry powder composition for topical delivery to the lungs by inhalation. Typically, the composition comprises a powder mix for inhalation of a peptide of the invention and a suitable powder base, diluent or carrier substance such as lactose, dextrose, dextran, mannitol or other sugar or starch. The composition may be used in any of a variety of dry powder devices, such as a container dry powder inhaler, a multidose dry powder inhaler or a metered dose inhaler. The composition may contain additional excipients, such as an alcohol, a surfactant, a lubricant, an antioxidant or a stabilizer. Suitable propellants include hydrocarbon, chlorofluorocarbon and hydrofluoroalkane propellants, or mixtures of any of these propellants. the

Inhalation solutions may also be formulated as a liquefied propellant for aerosol delivery, eg, using a pressurized metered dose inhaler. In yet another formulation, the solution may be an aerosolized aqueous suspension or solution as a single-dose or multi-dose device, with or without suitable pH or osmolarity adjustment. the

4.2 Uses for subcutaneous injection

In one aspect, a composition comprising one or more peptides of the invention is formulated for subcutaneous injection, one or more times per day, preferably before a meal, more preferably between about 1 hour and about between 3 hours. In another aspect, the composition is formulated as an injectable sustained release formulation. In one embodiment, a peptide of the invention is combined with a polyethylene glycol, such as polyethylene glycol 3350, and optionally one or more additional excipients or preservatives, including but not limited to excipients Formulations such as salt, polysorbate 80, sodium hydroxide or hydrochloric acid to adjust pH and the like. In another embodiment, a peptide of the invention is formulated with a poly(orthoester), which may be a poly(orthoester), and optionally one or more additional excipients. A self-catalyzed poly(orthoester) with various percentages of lactic acid in the polymer backbone. In one embodiment, a poly-D,L-lactic-co-glycolic acid polymer (PLGA polymer), preferably a PLGA polymer with one hydrophilic end group, such as PLGA from Boehringer Ingelheim GmbH (Ingelheim, Germany) is used. RG502H. These formulations can be prepared, for example, by combining a peptide of the invention in a suitable solvent such as methanol with a solution of PLGA in dichloromethane and adding polystyrene to it in a reactor under suitable mixing conditions. A continuous phase solution of vinyl alcohol. In general, any injectable and biodegradable polymer, viscous polymers are also preferred in a sustained release injectable formulation. The teachings of U.S. Patent Nos. 4,938,763, 6,432,438, and 6,673,767 and the biodegradable polymers and formulation methods disclosed therein are incorporated herein by reference. Depending on the concentration and amount of peptide, the rate of biodegradation of the polymer, and other factors known to those skilled in the art, the formulation may be an injection requiring weekly, monthly, or other cycles. the

4.3 Administration methods and uses for circulatory shock and related diseases, indications, symptoms and syndromes. the

In yet another aspect, the invention includes methods, optionally including monitoring a subject for symptoms of circulatory shock, before and after administration of a pharmaceutical composition comprising one or more peptides of the invention. Thus, one of the methods of the present invention may be used after suffering an injury that could lead to circulatory shock but before manifesting overt symptoms of cardiovascular shock, including stage I, II or III circulatory shock. - administering one or more peptides of the invention to a subject. the

When administered therapeutically, one or more peptides of the invention are provided at or after the onset of a shock symptom. Therapeutic administration of one or more peptides of the invention may further act to attenuate any symptoms or prevent the occurrence of additional symptoms. When administered to prevent shock ("prophylactic administration"), one or more peptides of the invention are provided prior to any visible or perceptible symptoms. Prophylactic administration of one or more peptides of the invention acts to attenuate subsequent symptoms or prevent symptoms altogether. Routes of administration of one or more peptides of the invention include, but are not limited to, topical, transdermal, intranasal, pulmonary, vaginal, rectal, oral, subcutaneous, intravenous, intraarterial, intramuscular, intraosseous, intraperitoneal, Epidural and intrathecal. the

4.4 The administration method and use for preventive treatment. the

The invention also relates to methods of preventing undesired cytokine expression by administering to a subject a therapeutically effective amount of one or more peptides of the invention immediately prior to the onset of the first symptoms. As used herein, the term "prophylaxis" when it refers to shock indicates the administration of a substance of the invention to a subject in order to prevent the perceptible development of one or more symptoms of shock or to attenuate one or more symptoms of shock. effects of shock symptoms. The term "prevention" also encompasses arresting or suppressing excessive or undesired cytokine expression, eg with a "cytokine storm". Thus, it is possible to "pre-treat" a subject, for example a subject in a surgical situation, by using the substances of the invention to prevent undesired cytokine expression or the occurrence of shock. When it refers to shock, the phrase "preventing the progression" is used to mean a disease designed to prevent the perceptible development of one or more additional shock symptoms in a patient who already exhibits one or more symptoms of shock A course of symptoms, and is also used to refer to the prevention of exacerbation of already existing symptoms of shock in a subject. Symptoms of shock encompassed by the prophylactic methods of the present invention include, but are not limited to, those highlighted herein, such as tachycardia, shallow or unstable breathing, and death. A subject at risk for shock can be identified based on the specific circumstances surrounding a subject. Similarly, a patient suffering from a bacterial or viral infection or exhibiting fever or hypotension may also be at risk for cytokine overexpression, shock, or an inflammatory disease or condition. the

In additional embodiments of the invention, the method is used to prevent cardiogenic shock, hypovolemic shock, and vasodilatory shock, each of which may be in any of the three aforementioned shock phases. In a specific embodiment of the invention, these methods are used to prevent cardiogenic shock. In another specific embodiment of the invention, these methods are used to prevent vasodilatory shock. In another more specific embodiment of the invention, these methods are used to prevent shock caused by sepsis or bacteremia. In an even more specific embodiment, these methods are used to prevent septic shock or bacteremic shock in stage I, II or III shock. In yet another embodiment, the methods of the invention are used to prevent hypovolemic shock. the

Similar to the method of treating shock described herein, one embodiment of the method of preventing shock of the present invention comprises the simultaneous administration of another substance and one or more peptides of the present invention or a derivative thereof. The scope of the invention is not limited to the identification of substances that can be administered concurrently with one or more peptides of the invention to prevent shock. For example, one or more peptides of the invention may be administered simultaneously with androstenediol, androstenediol or derivatives thereof, various vasopressin agonists, or other pharmaceutically active substances to prevent shock, said other drugs Active substances such as catecholamines or other alpha adrenergic agonists, alpha ₂ adrenergic agonists, beta adrenergic agonists or beta ₂ adrenergic agonists including but not limited to epinephrine, norepinephrine, dopamine, Isoproterenol, vasopressin, and dobutamine.

Alternatively, one or more peptides of the invention may be administered simultaneously with fluids or other substances capable of preventing or eliminating symptoms in a subject suffering from hypovolemic shock, vasodilatory shock or risk of cardiogenic shock. The type of fluid that may be administered concomitantly with one or more peptides of the invention should be specific to the surrounding circumstances of a particular subject at risk for shock. For example, fluids that can be administered concurrently with one or more peptides of the invention include, but are not limited to, saline solutions—such as sodium chloride and sodium bicarbonate—as well as whole blood, artificial blood substitutes, plasma, serum, serum albumin, and colloidal solution. Colloidal solutions include, but are not limited to, solutions containing hydroxyethyl starch, albumin, or plasma. In a specific embodiment of the invention, the fluid in the subject comprises one or more of saline solution, colloid solution, whole blood, artificial blood substitute, plasma or serum with one or more of the present The inventive peptide or a derivative thereof is administered concomitantly to a subject at risk of suffering from a hypovolemic shock such as hemorrhagic shock. the

4.5 Methods of administration and uses for inflammation-related applications, diseases, indications, conditions and syndromes. the

In yet another aspect, the invention includes methods, optionally including monitoring a subject for signs or symptoms of inflammation, inflammatory disease, or inflammatory disorder, before and after administration of one or more peptides of the invention. Thus, one of the methods of the present invention may be used following diagnosis of a condition, disease or syndrome that may result in an inflammatory response, but prior to manifesting inflammation, inflammatory disease or overt symptoms of an inflammatory condition One or more peptides of the invention are administered to a subject. The methods of treating or preventing inflammation, inflammatory disease or inflammatory condition described herein comprise administering to a subject a therapeutically effective amount of one or more peptides of the invention. As used herein, the terms "administer" and "administering" are used to mean introducing at least one compound into a subject. When administered for therapy, the substance is provided at or after the onset of inflammation, inflammatory disease, or a sign or symptom of an inflammatory condition. Therapeutic administration of such substances acts to attenuate any symptoms or prevent the occurrence of additional symptoms. When administered to prevent or limit inflammation, inflammatory disease, or prophylactic administration of an inflammatory condition, providing a medicament comprising one or more peptides of the invention prior to any visible or perceptible symptoms combination. Prophylactic administration of one or more peptides of the invention acts to attenuate subsequent symptoms or prevent symptoms altogether. Routes of administration of one or more peptides of the invention include, but are not limited to, topical, transdermal, intranasal, pulmonary, vaginal, rectal, oral, subcutaneous, intravenous, intraarterial, intramuscular, intraosseous, intraperitoneal, Epidural and intrathecal. the

4.6 Methods of administration and uses for eye diseases, indications, conditions and syndromes. the

For ophthalmic applications, in one aspect, one or more peptides of the invention are formulated into an ophthalmic dosage form and administered in the form of eye drops, eye drops, or using other ocular delivery systems. Emulsions, ointments, gels, ophthalmic inserts, biodegradable ophthalmic inserts, liposomes, microparticles, nanoparticles, nanospheres, or ion pairing formulations may also be employed, which in some cases may result in The ocular residence time of a peptide of the present invention is increased. In one embodiment, the ophthalmic formulation is a solution comprising between about 0.0000001% and about 5% (w/v) of a peptide of the invention or a salt thereof, alternatively about Between 0.000001% and about 0.2% (w/v) of a peptide of the invention or a salt thereof, or alternatively between about 0.00001% and about 0.2% (w/v) of a peptide of the invention peptide or a salt thereof. the

5.0 Production Methods. the

Generally, the peptides of the invention can be synthesized by solid phase synthesis and purified according to methods known in the art. Any well-known procedures utilizing various resins and reagents can be used to prepare the peptides of the present invention. the

The cyclic peptides of the present invention can be easily synthesized by the known conventional procedure of forming a peptide bond between amino acids. These routine procedures include, for example, combining the free alpha amino group of one amino acid or its residue with its carboxyl group and other reactive groups protected with another amino acid with its amino group or other reactive groups protected. Any solution phase procedure of condensation between free primary carboxyl groups of its residues. In a preferred routine procedure, said cyclic peptides of the invention can be synthesized by solid phase synthesis and purified according to methods known in the art. Any of the well-known procedures utilizing various resins and reagents can be used to prepare the peptides of the present invention. the

The process of synthesizing said cyclic peptides can be carried out by a procedure in which each amino acid in the desired sequence is added sequentially one at a time to another amino acid or residue thereof, or first conventionally synthesized with the desired amino acid sequence The peptide fragments are then condensed to provide the desired peptide. The resulting peptide is then cyclized to produce a cyclic peptide of the invention. the

Solid phase peptide synthesis methods are well known and practiced in the art. In these methods, the peptide synthesis of the present invention can be carried out by sequentially incorporating the desired amino acid residues one at a time into the growing peptide chain according to the general principles of solid phase methods. These methods are disclosed in many references, including Merrifield, RB "Solid phase synthesis (Nobel lecture)" (Angew Chem 24:799-810 (1985)) and Barany et al., " The Peptides, Analysis, Synthesis and Biology" Volume 2 (Gross, E. and Meienhofer, J., Eds., Academic Press (Academic Press) 1-284 (1980)).

In the chemical synthesis of peptides, the reactive side chain groups of each amino acid residue are protected with a suitable protecting group, which prevents chemical reactions at this site until the protecting group is removed. It is also common to protect the alpha amino group of an amino acid residue or fragment that reacts at the carboxyl group as a whole, followed by selective removal of the alpha amino protecting group to allow a subsequent reaction at that site. Specific protecting groups have been disclosed and are known in solid phase synthetic methods as well as in solution phase synthetic methods. the

The alpha amino group can be protected with a suitable protecting group, including a carbamate-type protecting group such as benzyloxycarbonyl (Z) and substituted benzyloxycarbonyl such as p-chlorobenzyloxycarbonyl, p-nitrobenzyl Oxycarbonyl, p-bromobenzyloxycarbonyl, p-diphenylisopropoxycarbonyl, 9-fluorenylmethoxycarbonyl (Fmoc), and p-methoxybenzyloxycarbonyl (Moz); and aliphatic carbamate-type protecting groups , such as tert-butoxycarbonyl (Boc), diisopropylmethoxycarbonyl, isopropoxycarbonyl and allyloxycarbonyl (Alloc). Fmoc is preferred for alpha amino protection. the

The guanidino group can be protected with a suitable protecting group such as nitro, p-toluenesulfonyl (Tos), Z, pentamethylchromanesulfonyl (Pmc), adamantyloxycarbonyl, pentamethyldihydrobenzene andfuran-5-sulfonyl (Pbf) and Boc. the

Pbf and Pmc are preferred protecting groups for Arg. the

The peptides of the invention described herein are prepared using solid phase synthesis, e.g., with the aid of a Symphony Multiplex Peptide Synthesizer (Rainin Instrument Company) automated peptide synthesizer, using the program modules provided by the manufacturer and following the protocol set forth in the manufacturer's instructions. . the

Solid phase synthesis starts from the C-terminus of the peptide by coupling a protected alpha amino acid to a suitable resin. This starting material is obtained by attaching an α-amino-protected amino acid via an amide bond to a Sieber amide resin (9-Fmoc-aminoxanthen-3-yloxy-Merrifield resin) or Rink amide resin (4-(2 ',4'-dimethoxyphenyl-Fmoc-aminomethyl)phenoxy resin), attached via an ester bond to a p-benzyloxybenzyl alcohol (Wang) resin, a 2-chlorotris benzyl chloride resin or an oxime resin, or by other means well known in the art. The resin is loaded with amino acids sequentially through the necessary repeated cycles. The α-amino Fmoc protecting group is removed under basic conditions. For this purpose piperidine, piperazine, diethylamine or morpholine (20-40% v/v) in N,N-dimethylformamide (DMF) can be used. the

After removal of the alpha amino protecting group, the subsequently protected amino acids are coupled stepwise in the desired order to obtain an intermediate, protected peptide-resin. Activating reagents for coupling the amino acids in the solid phase synthesis of the peptides are well known in the art. After peptide synthesis, the orthogonally protected side chain protecting groups can be removed, if desired, to further derivatize the peptide using methods well known in the art. the

Typically, orthogonal protecting groups are used as appropriate. For example, the peptides of the invention contain amino acids with an amino group-containing side chain. In one aspect, an allyl-allyloxycarbonyl (Allyl-Alloc) protection scheme is employed, in which amino acids form a lactam bridge through their side chains, and orthogonal protecting groups that are cleavable under different reaction conditions are used for Other amino acids with side chains containing amino groups. Thus, for example, Fmoc-Lys(Alloc)-OH, Fmoc-Orn(Alloc)-OH, Fmoc-Dap(Alloc)-OH, Fmoc-Dab(Alloc)-OH, Fmoc-Asp(OAll)-OH or Fmoc The -Glu(OAll)-OH amino acid can be used to form a lactam bridge site by cyclization, while other amino acids with amino group-containing side chains have a different orthogonal protecting group, such as with Fmoc-Arg(Pbf )-OH, Fmoc-Lys(Boc)-OH, Fmoc-Dab(Boc)-OH, etc. Other protecting groups can also be used; by way of example but not limitation, Mtt/OPp (4-methyltrityl/2-phenylisopropyl) whose side chain forms a lactam bridge by cyclization , orthogonal protecting groups for other positions that are not cleavable with conditions suitable for cleavage of Mtt/OPp. the

Reactive groups in peptides can be selectively modified during solid phase synthesis or after removal from the resin. For example, the peptide can be modified on the resin to obtain an N-terminal modification, such as acetylation, or it can be removed from the resin using a cleavage reagent and then modified. Similarly, methods of modifying amino acid side chains are well known to those skilled in the art of peptide synthesis. The choice of reactive groups present on the peptide for modification is determined in part by the desired characteristics in the peptide. the

In the peptides of the invention, in one embodiment, the N-terminal group is modified by introducing an N-acetyl group. In one aspect, a method is employed wherein, after removal of the protecting group at the N-terminus, the resin-bound peptide is dissolved in N,N-dimethylformamide (DMF) in the presence of an organic base such as pyridine. react with acetic anhydride. Other N-terminal acetylation methods are known in the art, including solution phase acetylation, and may be employed. the

In one embodiment, the peptide can be cyclized prior to cleavage from the peptide resin. To deprotect the desired side chain by cyclization of the reactive side chain moiety, the peptide is suspended in a suitable solvent and a cyclic coupling reagent is added. Suitable solvents include, for example, DMF, dichloromethane (DCM) or 1-methyl-2-pyrrolidone (NMP). Suitable cyclic coupling reagents include, for example, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), 2-(1H- Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), benzotriazol-1-yl-oxy-tris(dimethylamino)phosphorus hexafluoro Phosphate (BOP), benzotriazol-1-yl-oxy-tris(pyrrolidinyl)phosphonium hexafluorophosphate (PyBOP), 2-(7-aza-1H-benzotriazol-1-yl )-1,1,3,3-tetramethylurea tetrafluoroborate (TATU), 2-(2-oxo-1(2H)-pyridyl)-1,1,3,3-tetramethyl Urea tetrafluoroborate (TPTU) or N,N'-dicyclohexylcarbodiimide/1-hydroxybenzotriazole (DCCI/HOBt). Couplings are conventionally initiated by using a suitable base such as N,N-diisopropylethylamine (DIPEA), sym-collidine or N-methylmorpholine (NMM). the

For peptides with a non-lactam cyclic bridge, such as peptides containing this bridge:

-(CH ₂ ) _x -NH-C(=O)-(CH ₂ ) _z -C(=O)-NH-(CH ₂ ) _y -,

Where x, y and z are each independently 1 to 5, the peptides can be produced using solid phase synthesis employing a side chain protected diamine amino acid for the position to be cyclized. the

Particularly preferred at these positions are diaminopyridine (Dap), diaminobenzidine (Dab) or Lys, preferably with an amine protecting group such as Alloc, Mtt, Mmt (methoxytrityl), Dde (1 -(4,4-Dimethyl-2,6-dioxocyclohex-1-ylidene)ethyl), ivDde(1-(4,4-Dimethyl-2,6-dioxocyclo Hex-1-ylidene)-3-methylbutyl) or any other orthogonally cleavable protecting group. Typically, one side chain protecting group is removed first, such as Mtt with 2% trifluoroacetic acid (TFA) in dichloromethane. After washing the resin, the resulting resin bound unprotected amine is acetylated eg with a 0.5M solution of a cyclic anhydride such as succinic anhydride or glutaric anhydride in dichloromethane/pyridine 1:1. After an additional washing step, the orthogonally cleavable protecting group for the second diamine amino acid was cleaved, eg Alloc was removed with tetrakis(triphenylphosphine)palladium(0) and phenylsilane in dichloromethane. After washing with dichloromethane and DMF, the resin-bound peptide is cyclized using standard coupling reagents such as TBTU and a base. Alternatively, an ivDde-protected resin-bound diamine amino acid can be deprotected with a 5% solution of hydrazine in DMF, and after washing with DMF, the resulting resin-bound amine can be acetylated with a cyclic anhydride Alternatively, it can be cyclized with a resin-bound carboxylic acid. the

Then, any suitable reagent such as ethylamine in DCM or a combination of different agents such as trifluoroacetic acid (TFA), triisopropylsilane (TIS), dimethoxybenzene (DMB), water, etc. Phase split these cyclized peptides. Dry the resulting crude peptide and fragment the remaining amino acid sides using any suitable reagent such as TFA, TIS, 2-mercaptoethane (MD) and/or 1,2-ethanedithiol (EDT) in the presence of water Chain protecting group (if any). The final product was precipitated by addition of cold ether and collected by filtration. Final purification is by reverse phase high performance liquid chromatography (RP-HPLC) using a suitable column such as a C ₁₈ column, but other separation or purification methods, such as those based on the size or charge of the peptides, may also be used. Once purified, peptides can be identified by any method such as high performance liquid chromatography (HPLC), amino acid analysis, mass spectrometry, etc.

For peptides of the invention having a C-terminally substituted amide derivative or N-alkyl group, the synthesis can proceed by solid phase synthesis by combining a protected alpha amino acid with a suitable resin Coupling starts from the C-terminus of the peptide. Methods for the preparation of such substituted amide derivatives on solid phase have been described in the art. See, e.g., "Synthesis of an array of amides by aluminum chloride assisted cleavage on resin bound esters by aluminum chloride assisted cleavage on resin bound esters" by Barn, D.R. et al. (Tetrahedron Letters, 37:3213-3216 (1996)); DeGrado, W.F and Kaiser E.T. "Solid-phase synthesis of protected peptides on a polymer-bound oxime: preparation of fragments containing the sequence of a cytotoxic 26-peptide analogue". (Solid-phase synthesis of protected peptides on a polymer bound oxime:Preparation of segments comprising the sequences of a cytotoxic 26-peptide analogue)" (J.Org.Chem.), 47:3258-3261(1982) ). The starting material can be obtained by attaching an alpha-amino protected amino acid via an ester bond to a p-benzyloxybenzyl alcohol (Wang) resin or an oxime resin in a well-known manner. The peptide chain is extended with the desired amino acid sequence, the peptide is cyclized, and the peptide-resin is treated with a solution of an appropriate amine (eg, methylamine, dimethylamine, ethylamine, etc.). Peptides employing a p-benzyloxybenzyl alcohol (Wang) resin were cleaved from the resin with aluminum chloride in DCM, and peptides employing an oxime resin were cleaved with DCM. Another way to prepare a peptide with a C-terminally substituted amide is to attach an alkylamine to a formyl resin, such as 4-(4-formyl-3- Methoxyphenoxy)butyryl-AM resin (FMPB AM resin), followed by sequential incorporation of the desired amino acid residues using the general principles of solid-phase synthesis. the

Although the synthesis has been initially described with reference to solid phase Fmoc chemistry, it is to be understood that other chemical and synthetic methods can be used to make the cyclic peptides of the invention, by way of example and not limitation, Boc chemistry, solution chemistry and other chemical and synthetic methods Methods. the

6.0 Preparations. the

Depending on the desired route of administration, the formulation of a composition comprising one or more cyclic peptides of the invention may vary. Thus, the formulation may be suitable for subcutaneous or intravenous injection, topical application, ophthalmic application, nasal spray application, inhalation application, other transdermal application, and the like. the

6.1 Salt forms of the cyclic peptides of the present invention

The cyclic peptides of the present invention may be in any pharmaceutically acceptable salt form. The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like salts. Particularly preferred are the ammonium, calcium, lithium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins such as arginine, beet Alkali, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, meglumine, morpholine, piperazine, piperidine , polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc. the

When the cyclic peptide of the present invention is basic, acid addition salts can be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. These acids include acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, carboxylic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid , lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, malonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, propionic acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, trifluoro Acetic acid etc. The acid addition salts of the peptides of the invention are formed from the peptide and an excess of an acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, citric acid, Tartaric acid, maleic acid, succinic acid or methanesulfonic acid. Particularly useful are the acetate, ammonium acetate and trifluoroacetate salt forms. When the peptide of the invention contains an acidic moiety, suitable pharmaceutically acceptable salts may include alkali metal salts, such as sodium or potassium salts, or alkaline earth metal salts, such as calcium or magnesium salts. the

6.2 Pharmaceutical composition. the

The present invention provides a pharmaceutical composition, comprising a cyclic peptide of the present invention and a pharmaceutically acceptable carrier. The carrier can be a liquid formulation, preferably a buffered, isotonic aqueous solution. the

Pharmaceutically acceptable carriers also include excipients, such as diluents, carriers, etc., and additives, such as stabilizers, preservatives, solubilizers, buffers, etc., as described later. the

These cyclic peptide compositions of the present invention can be formulated or mixed into a pharmaceutical composition comprising at least one cyclic peptide of the present invention together with one or more pharmaceutically acceptable carriers, the pharmaceutically acceptable carrier including excipients, Such as diluents, carriers, etc., and additives, such as stabilizers, preservatives, solubilizers, buffers, etc., as desired. Formulation excipients may include polyvinylpyrrolidone, gelatin, hydroxycellulose, gum arabic, polyethylene glycol, manniton, sodium chloride and sodium citrate. For injection or other liquid administration formulations, water containing at least one or more buffer components is preferred, stabilizers, preservatives and solubilizers may also be employed. For solid administration formulations, any of various thickeners, fillers, bulking agents and carrier additives, such as starch, sugar, fatty acid, etc., may be used. For topical formulations, any of a variety of creams, ointments, gels, lotions, and the like may be employed. For most pharmaceutical formulations, the inactive ingredients will make up the majority of the formulation (by weight or volume). For pharmaceutical formulations, it is also contemplated that any of a variety of measured-release, slow-release or sustained-release formulations and additives may be employed whereby dosages may be formulated to effectively deliver a drug over time. A peptide of the invention. the

In general, the actual amount of a cyclic peptide of the invention administered to a patient can vary within a relatively wide range depending on the mode of administration, the formulation used, the response desired. the

In practice, these cyclic peptides of the present invention can be combined as an active ingredient with a drug carrier to form a mixture according to conventional pharmaceutical preparation techniques. The carrier can take various forms depending on the desired mode of administration, such as oral, parenteral (including intravenous), urethral, vaginal, nasal, buccal, sublingual and the like. In preparing oral dosage compositions, any usual pharmaceutical medium may be employed, for example water, glycols, oils, alcohols, flavorants, preservatives, coloring agents in the case of oral liquid preparations such as suspensions, elixirs and solutions. etc.; or in the case of oral solid preparations such as powder, hard and soft capsules and tablets, carriers such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrants can be used wait. the

Because of their ease of administration, tablets and capsules represent a preferred oral dosage unit form. Tablets may, if desired, be coated by standard aqueous or non-aqueous techniques. The amount of active peptide in such therapeutically effective compositions is such that an effective dosage will be obtained. In another preferred dosage unit form, a sublingual dosage form such as a sheet, wafer, tablet, etc. may be used. the

The tablets, pills, capsules, etc. may also contain a binder such as tragacanth, gum arabic, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrant such as corn starch, potato starch or seaweed acid; a lubricant such as magnesium stearate; and a sweetener such as sucrose, lactose or saccharin. When a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil. the

Various other materials can be employed as coatings or to modify the physical form of the dosage unit. For example, tablets may be coated with shellac, sugar, or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetener, methyl and propyl parabens as preservatives, a dye, and a flavoring such as cherry or Citrus spice. the

Cyclic peptides can also be administered parenterally. Solutions or suspensions of these active peptides can be prepared in water suitably mixed with a surfactant, such as hydroxy-propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. These preparations may optionally contain a preservative to prevent the growth of microorganisms. the

The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. In all cases, the dosage form must be sterile and must be fluid and syringeable. The dosage form must be stable under the conditions of manufacture and storage and must be protected against the contamination of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, a polyol such as glycerol, propylene glycol or liquid polyethylene glycol, suitable mixtures thereof, and vegetable oils. the

The cyclic peptides of the present invention can be used therapeutically by nasal administration. "Nasal administration"means any form of intranasal administration of any cyclic peptide of the invention. The peptides may be in an aqueous solution, such as one comprising saline, citrate, or other common excipients or preservatives. The peptides may also be in a dry or powder formulation. the

The cyclic peptides of the present invention can be formulated with various substances that increase the effective nasal absorption of drugs, including peptide drugs. These substances should increase nasal absorption without unacceptable damage to the mucous membranes. Of these, U.S. Patent Nos. 5,693,608, 5,977,070, and 5,908,825 teach a number of pharmaceutical compositions that may be employed, including absorption enhancers, the teachings of each of the foregoing patents and all references and patents cited therein are incorporated by reference. the

If in an aqueous solution, the cyclic peptide may be suitably buffered by saline, acetate, phosphate, citrate, or other buffer at any physiologically acceptable pH, usually about pH 4 to about pH 7. Combinations of buffers may also be used, such as phosphate buffered saline, a saline and acetate buffer, and the like. In the case of saline, a 0.9% saline solution can be used. In the case of acetate, phosphate, citrate, etc., a 50 mM solution may be used. In addition to buffers, a suitable preservative can be employed to prevent or limit the growth of bacteria and other microorganisms. One such preservative that can be used is 0.05% benzalkonium chloride. the

In another alternative embodiment, the cyclic peptides of the invention can be administered directly into the lung. Intrapulmonary administration can be performed by a metered dose inhaler, a device that allows self-administered metering of the peptide of the invention by a patient during inhalation. In an aspect of this embodiment, the cyclic peptide may be in dry and particulate form, for example particles between about 0.5 μm and 6.0 μm, whereby such particles have sufficient mass to remain on the lung surface without being exhaled, But also small enough so that it does not settle on airway surfaces before reaching the lungs. Dry powder particles can be produced using any of a variety of different techniques, including but not limited to micro-milling, spray drying, and quick-frozen aerosols followed by lyophilization. For microparticles, these peptides can be deposited in the deep lungs, thereby being rapidly and efficiently absorbed into the blood. Furthermore, since this approach does not require penetration enhancers, as is sometimes the case with transdermal, nasal or oral mucosal delivery. Any of a variety of inhalers may be employed, including propeller-based aerosols, nebulizers, single-dose dry powder inhalers, and multiple-dose dry powder inhalers. Commonly used devices today include metered-dose inhalation aerosols, which are used to deliver drugs to treat asthma, chronic obstructive pulmonary disease, and more. Preferred devices include dry powder inhalers, designed to form a fine powder mist or aerosol with a particle size always less than about 6.0 [mu]m. the

Particle size, including average size distribution, can be controlled by the manufacturing method. For microgrinding, factors such as the size of the grinding head, the speed of the rotor, and the processing time control the particle size. For spray drying, factors such as nozzle size, flow rate, and dryer heat control particle size. For production by quick-freezing aerosols followed by freeze-drying, factors such as nozzle size, flow rate, and concentration of the aerosol solution control particle size. These and other parameters can be used to control particle size. the

The cyclic peptides of the invention can be administered therapeutically by injection of a sustained release formulation. In one embodiment, a cyclic peptide of the invention is formulated with polyethylene glycol, such as polyethylene glycol 3350, and optionally one or more additional excipients and preservatives, for deep intramuscular injection such as For gluteal or deltoid injection of a formulation, the additional excipients and preservatives include but are not limited to excipients such as salt, polysorbate 80, sodium hydroxide or hydrochloric acid to adjust pH and the like. In another embodiment, a cyclic peptide of the invention is formulated with a poly(orthoester), which may be a poly(orthoester), and optionally one or more additional excipients. Autocatalyzed poly(orthoesters) with various percentages of lactic acid in the polymer backbone. In one embodiment, poly-D,L-lactic-co-glycolic acid polymers are employed. In general, any injectable and biodigestible polymer, viscous polymers are also preferred, may be employed in a sustained release injectable formulation. Alternatively, other sustained release formulations may be employed, including formulations allowing subcutaneous injection, which may include nano/microspheres (e.g. compositions comprising PLGA polymers), liposomes, emulsions (e.g. oil water-in-emulsions), gels, insoluble salts or oily suspensions. The formulation may be injected on a daily, weekly, monthly or other periodic basis depending on the concentration and amount of the cyclic peptide, the sustained release rate of the materials used and other factors known to those skilled in the art. the

6.3 Oral formulations of the peptides of the invention. the

In one aspect, the peptides of the invention are formulated for oral delivery. The peptide is preferably formulated and produced by encapsulating it in an enteric protectant, more preferably not releasing until the tablet or capsule has passed through the stomach and optionally a further part of the small intestine. In the context of this application it is to be understood that the term enteric coating or material refers to a coating or material which will pass through the stomach substantially intact but will disintegrate rapidly in the small intestine to release the active drug substance. One enteric coating solution that can be used comprises cellulose acetate phthalate, and optionally other ingredients such as ammonium hydroxide, triacetin, ethanol, methylene blue, and purified water. Cellulose acetate phthalate is a polymer that has been used in the pharmaceutical industry for enteric coating of individual dosage forms such as tablets and capsules, and is insoluble in water at a pH of less than about 5.8. An enteric coating comprising cellulose acetate phthalate provides protection from the acidic environment of the stomach, but begins to dissolve in the environment of the duodenum (pH approximately 6-6.5) and waits until the dosage form reaches the ileum (pH approximately 7-8) when completely dissolved. In addition to cellulose acetate phthalate, other enteric coating materials are known and can be used with the peptides of the invention, including but not limited to hydroxypropyl methylcellulose Polyvinyl succinate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, and methacrylic acid-methyl methacrylate copolymer. The enteric coating employed promotes dissolution of the dosage form primarily at one location outside the stomach, and can be selected such that the enteric coating dissolves at a pH of about at least 6.0, more preferably a pH of about 6.0 to about 8.0. In a preferred aspect, the enteric coating dissolves and disintegrates near the ileum. the

Any of a variety of penetration enhancers may be employed to increase intestinal uptake as the enteric coating dissolves. In one aspect, penetration enhancers increase paracellular or transcellular transport systems. Increased paracellular transport can be achieved by opening the tight junctions of the cell; increased transcellular transport can be achieved by increasing the fluidity of the cell membrane. Typical, non-limiting examples of such penetration enhancers include calcium chelators, bile salts (such as sodium cholate), and fatty acids. The peptides of the invention may be an enteric coated individual dosage form comprising a fatty acid such as oleate, palmitate, stearate in an enteric capsule to increase paracellular transport , sodium caprate or conjugated linoleic acid. the

In one aspect, the individual dosage form, such as a tablet or capsule, optionally further comprises conventional pharmaceutical binders such as povidone, diluents, glidants, fillers such as microcrystalline Cellulose, lubricants such as magnesium stearate, disintegrants such as croscarmellose sodium, preservatives, coloring agents, etc. In some embodiments, peptides or polypeptides that are substrates for enteric proteases may further be added. the

6.4 Ophthalmic preparations. the

In one embodiment, ocular diseases, indications, conditions and syndromes, such as dry eye or uveitis, may be treated with an ophthalmic dosage form comprising one or more peptides of the invention. The ophthalmic dosage form may comprise, in addition to one or more peptides of the invention, one or more active ingredients, such as artificial tear components, topical corticosteroids, non-steroidal anti-inflammatory drugs, or calcineurin inhibitors. Agents such as cyclosporine-A (Restasis -Allergan). In a related embodiment, one or more compounds may be administered separately from one or more peptides of the invention, for example, separately in an ophthalmic dosage form comprising an artificial tear component, a topical cortical Steroids, a non-steroidal anti-inflammatory drug, a calcineurin inhibitor such as cyclosporine-A, or a combination of any of the foregoing.

Preferably, the eye drops are maintained at a pH in the range of about pH 3.5 to 9.0, preferably about pH 6.5 and pH 7.2, with a suitable buffer. The pH can be adjusted by any known means, such as by using HCl or NaOH. Buffers can include acetate, boric acid, sodium borate, potassium citrate, citric acid, sodium bicarbonate, tris (TRIS), various mixed phosphate buffers (e.g. Na ₂ HPO ₄ , NaH ₂ Combination of PO ₄ and KH ₂ PO ₄ ) and mixtures thereof. Typically, buffers will be used in amounts of about 0.05% to 2.5% (w/v), preferably about 0.1% to 1.5%; buffers should be as close to physiological ion concentrations as possible to minimize potential irritation, but still Maintain drug product pH during the shelf life of the product.

The eye drops used in the present invention may be made from purified water and, in one aspect, preferably a saline solution. Additional tonicity enhancers may be employed, including ionic or nonionic tonicity enhancers or both. Ionic osmotic pressure enhancers include alkali metal or alkaline earth metal halides, such as _CaCl2 , KBr, KCl, LiCl, NaI, NaBr, NaCl, _{Na2SO4 ,} or boric acid. Nonionic osmotic pressure enhancers include urea, glycerin, sorbitol, mannitol, propylene glycol, or dextrose. Typically, aqueous solutions of the invention are adjusted to an osmotic pressure approximately equivalent to that of a 0.9% (v/v) sodium chloride solution or a 2.5% glycerol solution with osmolarity adjusting agents. However, an osmolality range corresponding to between 0.7% NaCl and 1.5% NaCl is generally considered acceptable.

These solutions may also contain conventional pharmaceutically acceptable preservatives, stabilizers, solubilizers and/or penetration enhancers as well as viscoelastic substances contained in artificial tear preparations. Pharmaceutically acceptable preservatives include quaternary ammonium compounds such as benzalkonium chloride, benzoammonium chloride, etc.; alkylmercury salts of thimerosalic acid such as thimerosal, phenylmercuric nitrate, phenylmercuric acetate or borate; sodium perborate; Sodium chlorite; parabens such as methylparaben or propylparaben; alcohols such as chlorobutanol, benzyl alcohol or phenylethyl alcohol; guanidine derivatives such as chlorhexidine or polyhexa Methylene biguanide; sorbic acid; boric acid; or a peroxide-forming preservative, or a combination of two or more of the foregoing. Pharmaceutically acceptable antioxidants and chelating agents can be used, including various sulfites (such as sodium metabisulfite, sodium thiosulfate, sodium bisulfite, or sodium sulfite), alpha-tocopherol, ascorbic acid, acetylcysteine, 8-hydroxyquinolome (8-hydroxyquinolome), antipyrine, butylated hydroxyanisole or butylated hydroxytoluene, ethylenediaminetetraacetic acid (EDTA), etc. Co-solvents such as alcohols and the like can also be used. Formulation stability can also be enhanced with different substances, for example cyclodextrins. the

20）、对羟基苯甲酸酯、皂苷、各种聚氧乙烯醚化合物如Brij 

35、Brij 

78或者Brij 

98、乙二胺四乙酸（EDTA）、胆汁盐和胆汁酸（如胆酸钠、牛磺胆酸钠、甘氨脱氧胆酸钠、牛磺脱氧胆酸钠、牛磺胆酸、鹅去氧胆酸和熊去氧胆酸）、癸酸、氮酮、夫西地酸（fucidic acid）、环六亚甲基月桂酰胺（hexamethylene lauramide）、皂苷、环六亚甲基辛酰胺（hexamethylene octanamide）和癸甲基亚砜。也可以采用离子配对配制品来降低化合物的亲油性，从而提高角膜渗透性，所述离子配对配制品使用带电荷的赋形剂或者抗衡离子以保护/中和药物分子上的带电荷基团。在其他带电荷的离子配对剂中，这些配制品包括但不限于离子如山梨酸、硼酸和马来酸。  Penetration enhancers can be used in eye drops and include compounds such as surfactants, certain organic solvents such as dimethyl sulfoxide and other sulfoxides, dimethylacetamide and pyrrolidine, certain amides of heterocyclic amines, di Alcohols (such as propylene glycol), propylene carbonate, oleic acid, alkylamines and derivatives, various cationic, anionic and nonionic surfactants, amphoteric surfactants, etc. Additional penetration enhancers that may be employed include cetylpyridinium chloride, ionophores such as lasalocid, benzalkonium chloride, polysorbates such as polysorbate 20 (Tween

20), parabens, saponins, various polyoxyethylene ether compounds such as Brij

35. Brij

78 or Brij

98. Ethylenediaminetetraacetic acid (EDTA), bile salts and bile acids (such as sodium cholate, sodium taurocholate, sodium glycodeoxycholate, sodium taurodeoxycholate, taurocholic acid, chenodeoxy Cholic acid and ursodeoxycholic acid), capric acid, azone, fucidic acid, hexamethylene lauramide, saponins, hexamethylene octanamide and decylmethylsulfoxide. Ion-pairing formulations using charged excipients or counterions to protect/neutralize charged groups on the drug molecule can also be used to reduce the lipophilicity of the compound, thereby increasing corneal permeability. These formulations include, but are not limited to, ions such as sorbic acid, boric acid, and maleic acid, among other charged ion pairing agents.

Viscosity enhancers or lubricants may be employed as necessary or appropriate. In one aspect, the viscosity enhancing agent comprises a water soluble polymer, such as a polyol, including polyvinyl alcohol, polyethylene glycol, or a combination of water soluble polymers. In one aspect, polyethylene glycol 300 or 400 is employed. The content of water soluble polymer may be between about 0.25% and about 4.0% (w/v). Thus, an eye drop may contain, for example, 1% polyvinyl alcohol, 1% polyethylene glycol 300 or 400, or both. Other polyols may be employed, including glycerol, glycerin, polysorbate 80, propylene glycol, ethylene glycol, povidone, and polyvinylpyrrolidone. Other lubricants, sometimes called tear substitutes, are also available, including cellulose derivatives such as hydroxypropylmethylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, and methylcellulose Cellulose; dextrans such as Dextran 70; water-soluble proteins such as gelatin; carbomers such as Carbomer 934P, Carbomer 941, Carbomer 940 and Carbomer 974P; and gums such as Hydroxypropyl Guar Gum (HP- guar), xanthan gum, or combinations thereof. Other viscosity enhancing agents that may be employed include polysaccharide compounds, such as sulfated or non-sulfated glycosaminoglycan compounds. In one aspect, the polysaccharide compound is a non-sulfated glycosaminoglycan, such as hyaluronic acid or a pharmaceutically acceptable salt thereof, such as sodium hyaluronate. Hyaluronic acid and salts thereof of any commercially available molecular weight range can be used. About 0.05% to about 0.4% (w/v) of hyaluronic acid or a salt thereof can be used in an eye drop. In another aspect, the polysaccharide compound is a non-sulfated glycosaminoglycan such as dextran. In yet another aspect, the polysaccharide is a sulfated glycosaminoglycan such as chondroitin sulfate. the

934P、聚卡波菲以及具有Pluronic 

聚氧烯醚的CMC或PAA；或者聚阳离子聚合物如壳聚糖。也可以采用乳剂（水包油或者油包水），包括微乳剂，所述乳剂由药学上可接受的油以及增粘剂、防腐剂、助溶剂、表面活性剂和其他物质中的一种或多种组成。药学上可接受的油包括矿物油和有机油，包括包含中链或长链饱和或不饱和脂肪酸或其酯的油。因此，药学上可接受的油包括任何范围的中链甘油三酯，以及油如杏仁油、蓖麻油、棉花籽油、甘油（glycerin，glycerol）、花生油、矿物油、聚乙二醇、罂粟籽油、丙二醇、红花油、芝麻油、大豆油、橄榄油和植物油。也可以采用一种表面活性剂如一种聚氧乙烯烷基醚、聚氧蓖麻油（polyoxyl castor oil）、泰洛沙泊、烷基芳基醚磺酸盐、卵磷脂、脱水山梨糖醇酯、单硬脂酸甘油酯、十六醇、辛苯醇醚-9、壬苯醇醚-9、聚氧乙烯硬脂酸盐、聚氧乙烯脱水山梨糖醇脂肪酸酯如聚山 梨醇酯20、60和80等。也可以采用水凝胶，其往往由聚合物如聚乙烯醇（PVA）、聚丙烯酰胺、泊洛沙姆、羟丙基甲基纤维素（HPMC）、卡波姆、聚甲基乙烯基醚马来酸酐和羟丙基乙基纤维素组成。可以使用含有可膨胀、不溶于水的聚合物的水凝胶（hydrogel），所述水凝胶含有聚合物如聚(丙烯酸)、聚(丙烯酸类)、聚(丙烯酰胺)和乙烯马来酸酐，以及化学或热处理的明胶。也可以使用眼用嵌入剂、脂质体、discome、类脂质体（niosome）、树状高分子（dedrimer）、纳米悬浮液、纳米颗粒和微颗粒，以控制释放药物。脂质体和其他控释物质可以带正电荷，以通过与带负电荷的角膜表面的离子相互作用而提高停留时间。纳米颗粒可以由可生物降解的聚合物如聚乳酸（PLA）、聚腈基丙烯酸酯、聚(D,L-丙交酯)以及天然聚合物如壳聚糖、明胶、海藻酸钠、白蛋白等组成。  Semi-solid formulations can be used for ophthalmic delivery to increase the corneal residence time of drug molecules. Ointments containing polyethylene glycol, lanolin alcohol, ozokerite, ceresin, microcrystalline wax, surfactants, preservatives, sorbitan monolaurate, white petrolatum may be used and light liquid paraffin (mineral oil) or other petrolatum-like base. Aqueous or non-aqueous suspensions can be used. For hydrophilic peptides, suspensions using pharmaceutically acceptable salts or petrolatum can be used. Suspensions may contain microspheres or microparticles, nanoparticles, mucoadhesive particles, viscosity increasing agents, surfactants and other substances. Mucoadhesive compounds include synthetic polymers such as polyacrylic acid and polycarbophil; biopolymers such as hyaluronic acid or sodium carboxymethylcellulose (CMC); polyanionic polymers such as polyacrylic acid (PAA); polyacrylic acids such as Carbopol

934P, polycarbophil and with Pluronic

CMC or PAA of polyoxyalkylene ethers; or polycationic polymers such as chitosan. Emulsions (either oil-in-water or water-in-oil), including microemulsions, consisting of a pharmaceutically acceptable oil and one or more of a viscosity builder, preservative, solubilizer, surfactant, and other substances may also be employed. Various compositions. Pharmaceutically acceptable oils include mineral oils and organic oils, including oils containing medium or long chain saturated or unsaturated fatty acids or esters thereof. Thus, pharmaceutically acceptable oils include any range of medium chain triglycerides, as well as oils such as almond oil, castor oil, cottonseed oil, glycerin (glycerol), peanut oil, mineral oil, polyethylene glycol, poppy seed Oil, Propylene Glycol, Safflower Oil, Sesame Oil, Soybean Oil, Olive Oil and Vegetable Oil. A surfactant such as a polyoxyethylene alkyl ether, polyoxyl castor oil, tyloxapol, alkyl aryl ether sulfonate, lecithin, sorbitan ester, Glyceryl monostearate, cetyl alcohol, octoxynol-9, nonoxynol-9, polyoxyethylene stearate, polyoxyethylene sorbitan fatty acid esters such as polysorbate 20, 60 and 80 etc. Hydrogels can also be used, which are often composed of polymers such as polyvinyl alcohol (PVA), polyacrylamide, poloxamers, hydroxypropylmethylcellulose (HPMC), carbomer, polymethylvinyl ether Composed of maleic anhydride and hydroxypropyl ethyl cellulose. Hydrogels containing swellable, water-insoluble polymers containing polymers such as poly(acrylic acid), poly(acrylic acid), poly(acrylamide), and ethylene maleic anhydride can be used , and chemically or heat-treated gelatin. Ophthalmic embedders, liposomes, discomes, niosomes, dendrimers, nanosuspensions, nanoparticles, and microparticles can also be used for controlled drug release. Liposomes and other controlled release materials can be positively charged to increase residence time through ionic interactions with the negatively charged corneal surface. Nanoparticles can be made of biodegradable polymers such as polylactic acid (PLA), polycyanoacrylate, poly(D,L-lactide), as well as natural polymers such as chitosan, gelatin, sodium alginate, albumin and so on.

6.5 Route of Administration of Preparations. the

If a formulation comprising one or more peptides of the invention is administered by injection, the injection may be intravenous, subcutaneous, intramuscular, intraperitoneal or otherwise known in the art. The peptides of the invention may be formulated by any means known in the art, including but not limited to formulation as tablets, capsules, caplets, suspensions, powders, lyophilized formulations, suppositories, eye drops, skin patches , oral dissolving formulations, sprays, aerosols, etc., and can be mixed and formulated with buffers, binders, excipients, stabilizers, antioxidants and other substances known in the art. In general, any route of administration that introduces the peptides of the present invention through the epidermis of cells can be used. Therefore, the mode of administration may include administration through mucous membranes, buccal administration, oral administration, transdermal administration, inhalation administration, nasal administration, transurethral administration, vaginal administration and the like. the

6.6 Therapeutically effective dose. the

In general, the actual amount of a cyclic peptide of the invention administered to a patient will vary within a wide range depending on the mode of administration, the formulation used and the response desired. Dosages for treatment are administered by the foregoing means and any other means known in the art in amounts sufficient to bring about the desired therapeutic effect. A therapeutically effective amount thus includes an amount of a peptide or pharmaceutical composition of the invention sufficient to therapeutically alleviate sexual dysfunction in a patient or to prevent or delay the onset or recurrence of sexual dysfunction. the

In general, these cyclic peptides of the invention are highly active. For example, about 0.1, 0.5, 1, 5, 50, 100, 500 can be administered depending on the particular peptide selected, the desired therapeutic response, the route of administration, the formulation, and other factors known to those skilled in the art. , 1000 or 5000 μg/kg body weight of the cyclic peptide. the

7.0 Peptides of the Invention. the

In one aspect, the invention provides a cyclic peptide comprising a core sequence derived from His-Phe-Arg in the cyclic portion, but excluding Trp in the cyclic portion, wherein Trp or a derivative thereof or A mimetic (defined as an amino acid residue having a side chain, including but not limited to Nal 1 or Nal 2, that includes at least one aryl or heteroaryl group) is on the C-terminal side immediately outside the ring moiety amino acid residues. The sequence is thus derived from His-Phe-Arg- ^Xaa6 -Trp, where ^Xaa6 is an amino acid whose side chain forms a cyclic bridge with the side chain of another amino acid or the N-terminal group of the peptide.

The core sequence derived from His-Phe-Arg- ^Xaa6 -Trp may include many substitutions. The His position can be His, or can be a substituted or unsubstituted Pro or an amino acid with a side chain comprising at least one primary amine, secondary amine, alkyl, cycloalkyl, cycloheteroalkane radical, aryl, heteroaryl, alcohol, ether, sulfide, sulfone, sulfur oxide, carbonyl (carbomyl) or carboxyl. Substituted Pros include, but are not limited to, amino acids such as Hyp, Hyp(Bzl), Pro(4R-Bzl) or Pro(4R- _NH2 ). The Phe position may be Phe, but more typically is substituted or unsubstituted D-Phe, D-Nal 1, D-Nal 2 or an amino acid with a side chain including a pyridyl group. The Arg position may be Arg, Lys, Orn, Dab or Dap, or a substituted or unsubstituted Pro, or Cit, or may be an amino acid with a side chain comprising at least one primary, secondary, Amine, guanidine, urea, alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl or ether. Xaa6 can be an amino acid with a side chain including a primary amine, such as Lys, Orn, Dab, Dap, or an amino acid with a carboxyl group, such as Asp, Glu or hGlu, or an amino acid with a disulfide group Amino acids, such as Cys or Pen, all depend on the nature of the cyclic bridge. The Trp position may be an amino acid with a side chain, such as Trp, Nal 1 or Nal 2, comprising at least one substituted or unsubstituted aryl or heteroaryl group.

Therefore the present invention provides a kind of cyclic peptide of formula (VII):

Z-Xaa ¹ -Xaa ² -Xaa ³ -Xaa ⁴ -Xaa ⁵ -Xaa ⁶ -Xaa ⁷ -Y (VII)

or a pharmaceutically acceptable salt thereof, wherein:

Z is H or an N-terminal group;

Xaa ¹ is optionally present, and if present, it is one to three L- or D-isomer amino acid residues;

Xaa ² and Xaa ⁶ are L- or D-isomer amino acids, wherein their side chains include a cyclic bridge;

Xaa ³ is L- or D-Pro, optionally with hydroxyl, halogen, sulfonamide, alkyl, -O-alkyl, aryl, alkyl-aryl, alkyl-O-aryl, alkyl- O-alkyl-aryl or -O-aryl substitution, or Xaa3 is an L- or D-isomer of an amino acid with a side chain comprising at least one primary, secondary, alkyl , cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, ether, sulfide, or carboxyl.

Xaa ⁴ is an L- or D-isomer amino acid having a side chain comprising phenyl, naphthyl or pyridyl, optionally wherein the ring is substituted with one or more substituents, so The substituents are independently selected from halogen, (C ₁ -C ₁₀ ) alkyl halide, (C ₁ -C ₁₀ ) alkyl, (C ₁ -C ₁₀ ) alkoxy, (C ₁ -C ₁₀ ) alkyl Sulfur, aryl, aryloxy, nitro, nitrile, sulfonamide, amino, monosubstituted amino, disubstituted amino, hydroxyl, carboxyl and alkoxy-carbonyl.

Xaa ⁵ is L- or D-Pro or Xaa ⁵ is an L- or D-isomer amino acid with a side chain comprising at least one primary amine, secondary amine, guanidine, urea, alkyl, ring Alkyl, cycloheteroalkyl, aryl, heteroaryl or ether.

^Xaa7 is optionally present, and if present, it is one to three L- or D-isomer amino acid residues; and

Y is a C-terminal group. the

In one aspect, Xaa ⁴ can be D-Phe, optionally substituted with one or more substituents independently selected from halogen, (C ₁ -C ₁₀ )alkyl halides, (C ₁ -C ₁₀ ) Alkyl, (C ₁ -C ₁₀ )alkoxy, (C ₁ -C ₁₀ )alkylthio, aryl, aryloxy, nitro, nitrile, sulfonamide, amino, monosubstituted amino, bis Substituted amino, hydroxy, carboxyl and alkoxy-carbonyl groups.

In another aspect, one of Xaa ² and Xaa ⁶ can be an L- or D-isomer of Asp, hGlu or Glu, and the other of Xaa ² and Xaa ⁶ is of Lys, Orn, Dab or Dap One L- or D-isomer. In another aspect, each of Xaa ² and Xaa ⁶ can be Cys, D-Cys, Pen or D-Pen.

In another aspect, Xaa ¹ can be an amino acid having a side chain comprising a linear or branched alkyl, cycloalkyl, cycloheteroalkyl, aryl, or heteroaryl.

In another aspect, ^Xaa7 can be an amino acid having a side chain comprising at least one aryl or heteroaryl, optionally substituted with one or more ring substituents, wherein when one or more substituents are present , the substituents are the same or different and are independently hydroxyl, halogen, sulfonamide, alkyl, -O-alkyl, aryl or -O-aryl.

In another aspect, the N-terminal group can be a _C1 to _C17 acyl group, wherein _C1 to _C17 includes a straight or branched chain alkyl, cycloalkyl, alkylcycloalkyl, aryl or alkylaryl, a straight or branched C ₁ to C ₁₇ alkyl, aryl, heteroaryl, alkene, alkenyl or aralkyl chain, or an N-acylated straight or branched C ₁ to C ₁₇ alkyl, aryl, heteroaryl, alkene, alkenyl or aralkyl chains.

On the other hand, Y can be a hydroxy group, an amide, or a C ₁ to C ₁₇ alkyl, cycloalkyl, aryl, alkylcycloalkyl, aralkyl, hetero Amides substituted with aryl, alkene, alkenyl or aralkyl chains.

Therefore the present invention provides on the one hand a kind of cyclic peptide of formula (VII) as defined above, but wherein

Xaa ⁴ is D-Phe, optionally substituted with one or more substituents independently selected from halogen, (C ₁ -C ₁₀ )alkyl halide, (C ₁ -C ₁₀ )alkyl, (C ₁ -C ₁₀ )alkoxy, (C ₁ -C ₁₀ )alkylthio, aryl, aryloxy, nitro, nitrile, sulfonamide, amino, monosubstituted amino, disubstituted amino, hydroxyl , carboxyl and alkoxy-carbonyl.

Xaa ⁵ is an L- or D-isomer of Arg, Lys, Orn, Dab or Dap; and

Xaa ⁷ is an L- or D-isomer of Trp, Nal 1 or Nal 2.

In the above, on the one hand, Xaa ³ can be an L- or D-isomer of His, on the other hand, Z can be a C ₁ to C ₁₇ acyl group and Xaa ¹ can be an L of Nle - or D-isomer.

In the above, in formula (I), substituted Pro may be, for example, Hyp, Hyp(Bzl), Pro(4-Bzl), and Pro(4-NH ₂ ).

The peptides contained in formulas (I) to (VII) contain one or more asymmetric elements, such as stereocenters, stereoaxes, etc., so that the peptides contained in formula (I) can be in different stereoisomers form exists. For specific and generically described peptides, including those contained in formulas (I) to (VI), all forms of isomers at all chiral or other isomeric centers, including enantiomers and non- Enantiomers are both intended to be encompassed herein. The peptides of the invention each comprise chiral centers and, in addition to being used in the preparation of enantiomers, can also be used as a racemic mixture or an enantiomerically enriched mixture. Typically, the peptides of the invention are synthesized using chirally pure reagents, such as the designated L- or D-amino acids, using reagents, conditions and methods to maintain enantiomeric purity, although production of racemic mixtures is contemplated. These racemic mixtures may optionally be separated using well known techniques and an individual enantiomer may be used individually. Given the particular temperature, solvent and pH conditions under which a peptide may exist in tautomeric forms, it is considered whether each tautomeric form contained in the present invention exists in equilibrium or exists primarily in one form. Thus, a single enantiomer of the peptide of formula (I), which is an optically active form. the

The present invention is further intended to include prodrugs of the peptides of the present invention which, after administration, undergo chemical transformation by metabolic processes before becoming active pharmacological peptides. Typically, these prodrugs will be functional derivatives of the peptides of the invention, which can be easily converted in vivo into the peptides of formulas (I) to (VII). A prodrug is any covalently bonded compound that releases the active parent peptide drug of formulas (I) to (VII) in vivo. General procedures for selecting and preparing suitable prodrug derivatives are described, for example, in "Design of Prodrugs" by ed. H. Bundgaard, Elsevier, 1985. Typical examples of prodrugs have biolabile protecting groups on one functional moiety, eg by esterifying hydroxyl, carboxyl or amino functions. Thus, by way of example and not limitation, a prodrug includes a peptide of formula (I) in the form of an ester prodrug, such as a lower alkyl ester of the R group of formula (I), for example wherein R is -OH, so The lower alkyl esters may contain 1-8 carbons in an alkyl group or the aralkyl esters may have 6-12 carbons in an aralkyl group. In a broad sense, prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrated, alkylated, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated to generate in vivo an active parent peptide drug compound of formula (I). the

The present invention also includes peptides identical to those described in formulas (I) to (VI), but in fact, one or more atoms described in formulas (I) to (VI) are represented by an atomic mass or atomic number Atom substitution with an atomic mass or atomic number different from that normally found in nature. Examples of isotopes that may be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen and oxygen such as ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O and ¹⁷ O, respectively. The peptides of the present invention and pharmaceutically acceptable salts or solvates of said compounds containing the above-mentioned isotopes and/or other isotopes of other atoms are within the scope of the present invention. Certain isotopically-labeled compounds of the invention, eg, those into which radioactive isotopes such ^{as3H and14C} are incorporated, are useful in various assays, eg, drug and/or substrate tissue distribution assays. Substitution with heavier isotopes, such as deuterium ( ^2H ), for one or more hydrogen atoms, may in some cases provide pharmacological advantages, including increased metabolic stability. Isotopically labeled peptides of formulas (I) to (VI) can generally be prepared by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

8.0 Tests and assays for evaluating the peptides of the invention. the

The melanocortin receptor-specific peptides of the invention can be tested in a variety of assay systems and animal models to determine binding, functional status and potency. the

8.1 Competitive inhibition assay using [I ¹²⁵ ]-NDP-α-MSH.

曲线拟合软件确定用于本发明的肽的Ki值。  Use membrane homogenates prepared from HEK-293 cells expressing recombinant hMCR-1a or hMCR-4 (in each case the h prefix refers to human) or alternatively with B16-F10 cells containing endogenous mouse MCR-1 Membrane homogenates of mouse melanoma cells were subjected to a competitive inhibition binding assay. In the examples below, all MCR-1 and MCR-4 values are for human recombinant receptors unless otherwise indicated. Assays were performed in 96-well polypropylene round-bottom plates (VWR Cat. No. 12777-030). Membrane homogenates were incubated with 0.1 nM [I ¹²⁵ ]-NDP-α-MSH (Perkin Elmer) and increasing concentrations of the test peptides of the invention in a buffer containing 100 mM NaCl, 2 mM CaCl ₂ , 2 mM MgCl ₂ , 0.3 mM 1,10-phenanthroline and 0.2% bovine serum albumin in 25 mM hydroxyethylpiperazineethanesulfonic acid (HEPES) buffer (pH 7.5). After incubation at 37°C for 90 minutes, the assay mixture was filtered on GF/B Unifilter plates (Perkin-Elmer Cat# 6005177) and washed with 3 mL of ice-cold buffer per well. Air dry the filters and add 35 μL of scintillation cocktail to each well. For bound radioactivity, plates were counted in a Microbeta counter. Non-specific binding was measured by inhibition of [I ¹²⁵ ]-NDP-α-MSH binding in the presence of 1 μM NDP-α-MSH. Maximum specific binding (100%) was defined as the difference in radioactivity (cpm) bound to the cell membrane in the presence or absence of 1 μM NDP-α-MSH. Each determination was performed in duplicate and actual mean values are depicted, with values less than 0% reported as 0%. Using Graph-Pad Prism

Curve fitting software determines the Ki values for the peptides used in the present invention.

8.2 Determination of Agonist Activity. the

cAMP细胞分析系统，使用穴状化合物标记的抗cAMP和d2标记的cAMP确定cAMP水平，平板在一种Perkin-Elmer Victor酶标仪上在665nM和620nM下读数。使用Graph-Pad Prism

软件通过非线性回 归分析进行数据分析。比较利用参照黑皮质素激动剂NDP-α-MSH获得的最大效力值，确定本发明的每种测试肽的最大效力（E_max）值。  Intracellular accumulation of cAMP was examined as a measure of the ability of the peptides of the invention to elicit a human melanoma cell line HBL expressing hMCR-1 (see Kang, L. et al., "A melanocortin-1 A selective small molecule agonist of melanocortin-1 receptor inhibits lipopolysaccharide-induced cytokine accumulation and leukocyte infiltration in mice" (Leukocyte Biology Biol. 80:897-904 (2006))) or functional responses in HEK-293 cells expressing hMCR-4. Confluent HBL cells expressing hMCR-1 or HEK-293 cells expressing recombinant hMCR-4 were detached from the culture plates by incubation in enzyme-free cell dissociation buffer. The dispersed cells were suspended in Earle's Balanced Salt Solution containing 10 mM HEPES (pH 7.5), 1 mM MgCl ₂ , 1 mM glutamine, 0.5% albumin and 0.3 mM 3 - Isobutyl-1-methyl-xanthine (IBMX) (a phosphodiesterase inhibitor). HBL cells were plated in a 96-well plate at a density of 0.4×10 ⁵ cells per well and HEK-293 cells were plated in a 96-well plate at a density of 0.5×10 ⁵ cells per well and pre-incubated for 10 minutes. Cells were exposed to peptides of the present invention in DMSO (final DMSO concentration 1%) at concentrations ranging from 0.05-5000 nM in a total assay volume of 200 μL for 15 minutes at 37°C. NDP-α-MSH was used as a reference agonist. By a HTRF-based from Cisbio Bioassay

cAMP Cellular Assay System, cAMP levels were determined using cryptate-labeled anti-cAMP and d2-labeled cAMP, and plates were read at 665 nM and 620 nM on a Perkin-Elmer Victor microplate reader. Using Graph-Pad Prism

The software performed data analysis by non-linear regression analysis. The maximum potency (E _max ) value for each test peptide of the invention was determined in comparison to the maximum potency value obtained with the reference melanocortin agonist NDP-α-MSH.

9.0 Examples. the

Peptides of the following structures were analyzed and mean MCR-1 and MCR-4 Ki values determined as indicated. All Ki values were determined using [I ¹²⁵ ]-NDP-α-MSH. All results are expressed in nM except E _max values, _which are percentage values.

Peptides with the primary sequences under the headings were analyzed and purified as described in Section 5 above, wherein the resulting peptides had the described structures. Following analysis and purification, each peptide was tested as described in Section 8 above and the results are shown below. the

9.1 Ac-Nle-cyclo(Glu-His-D-Phe-Arg-Lys)-Trp-NH ₂ (SEQ ID NO: 4)

9.2 Ac-Nle-cyclo(Glu-His-D-Phe-Arg-Dab)-Trp-NH ₂ (SEQ ID NO:5)

9.3 Ac-Nle-cyclo(Glu-His-D-Phe-Arg-Dap)-Trp-NH ₂ (SEQ ID NO:6)

9.4 Ac-Nle-ring (Asp-His-D-Phe-Arg-Dap)-Trp-NH ₂ (SEQ ID NO: 7)

9.5 Ac-Nle-cyclo(Cys-His-D-Phe-Arg-Cys)-Trp-NH ₂ (SEQ ID NO:8)

9.6 Ac-Nle-ring (Glu-His-D-Phe-Arg-Orn)-Trp-NH ₂ (SEQ ID NO: 9)

9.7 Ac-Nle-cyclo(Glu-His-D-Phe-Arg-Dab)-D-Trp-NH ₂ (SEQ ID NO: 10)

9.8 Ac-Nle-cyclo(Glu-His-Phe-Arg-Dab)-Trp-NH ₂ (SEQ ID NO: 11)

9.9 Ac-Nle-cyclo(Glu-His-D-Phe-Arg-Dab)-D-Nal 1-NH ₂ (SEQ ID NO: 12)

9.10 Ac-Nle-cyclo(Glu-His-D-Phe-Arg-Dab)-Nal 2 -NH ₂ (SEQ ID NO: 13)

9.11 Ac-Nle-ring (Glu-His-D-Phe-Arg-Dab)-D-Nal 2 -NH ₂ (SEQ ID NO: 14)

9.12 Ac-D-Phe-cyclo(Glu-His-D-Phe-Arg-Dab)-Trp-NH ₂ (SEQ ID NO: 15)

9.13 Ac-Phe-cyclo(Glu-His-D-Phe-Arg-Dab)-Trp-NH ₂ (SEQ ID NO: 16)

9.14 Cyclic (Suc-His-Phe-Arg-Dab)-Trp-NH ₂ (SEQ ID NO: 17)

9.15 CH ₃ -(CH ₂ ) ₂ -C(=O)-cyclo(Glu-His-D-Phe-Arg-Dab)-Trp-NH ₂ (SEQ ID NO: 18)

9.16 CH ₃ -(CH ₂ ) ₃ -C(=O)-cyclo(Glu-His-D-Phe-Arg-Dab)-Trp-NH ₂ (SEQ ID NO: 19)

9.17 CH ₃ -(CH ₂ ) ₄ -C(=O)-cyclo(Glu-His-D-Phe-Arg-Dab)-Trp-NH ₂ (SEQ ID NO:20)

9.18 CH ₃ -(CH ₂ ) ₅ -C(=O)-cyclo(Glu-His-D-Phe-Arg-Dab)-Trp-NH ₂ (SEQ ID NO:21)

9.19 Cyclo-propionyl-cyclo(Glu-His-D-Phe-Arg-Dab)-Trp-NH ₂ (SEQ ID NO:22)

9.20 Cyclo-hexanoyl-cyclo(Glu-His-D-Phe-Arg-Dab)-Trp-NH ₂ (SEQ ID NO:23)

9.21 Cyclopentylacetyl-cyclo(Glu-His-D-Phe-Arg-Dab)-Trp-NH ₂ (SEQ ID NO:24)

9.22 Cyclohexylacetyl-cyclo(Glu-His-D-Phe-Arg-Dab)-Trp-NH ₂ (SEQ ID NO:25)

9.23 Phenylacetyl-cyclo(Glu-His-D-Phe-Arg-Dab)-Trp-NH ₂ (SEQ ID NO:26)

9.24 Phenylpropionyl-cyclo(Glu-His-D-Phe-Arg-Dab)-Trp-NH ₂ (SEQ ID NO:27)

9.25 Ac-Nle-cyclo(Glu-His-D-Phe-Arg-Dab)-Ala-NH ₂ (SEQ ID NO: 28)

9.26 Ac-Nle-ring (Glu-His-D-Phe-Arg-Dap)-Trp-OH (SEQ ID NO: 29)

9.27 Ac-Nle-ring (Dab-His-D-Phe-Arg-Dab)-Trp-NH ₂ (SEQ ID NO: 30)

9.28 Ac-Nle-ring (Dap-His-D-Phe-Arg-Dap)-Trp-NH ₂ (SEQ ID NO: 31)

9.29 Ac-Nle-ring (Dab-His-D-Phe-Arg-Dap)-Trp-NH ₂ (SEQ ID NO: 32)

9.30 Ac-Nle-cyclo(Glu-His-D-Phe-Arg-Dab)-Nal 1-NH ₂ (SEQ ID NO: 33)

9.31 Ac-Nle-ring (Glu-His-D-Phe-Arg-Dab)-Trp-OH (SEQ ID NO: 34)

9.32 Ac-Nle-cyclo(Glu-His-D-Phe-Arg-Dab)-NH ₂ (SEQ ID NO:35)

9.33 Ac-Nle-cyclo(Glu-His-D-Phe-Ala-Dab)-NH ₂ (SEQ ID NO:36)

9.34 Ac-Nle-ring (Glu-His-D-Phe-Gly-Dab)-Trp-NH ₂ (SEQ ID NO: 37)

9.35 Ac-Nle-cyclo(Glu-His-D-Phe-Ala-Dab)-Trp-NH ₂ (SEQ ID NO:38)

9.36 Ac-Nle-cyclo(Glu-Ala-D-Phe-Arg-Dab)-Trp-NH ₂ (SEQ ID NO:39)

9.37 Ac-Nle-ring (Glu-Arg-D-Phe-Arg-Dab)-Trp-NH ₂ (SEQ ID NO: 40)

9.38 Ac-Nle-cyclo(Glu-Cit-D-Phe-Arg-Dab)-Trp-NH ₂ (SEQ ID NO:41)

9.39 Ac-Nle-cyclo(Glu-His-D-Phe-Arg-Dab)-Lys-NH ₂ (SEQ ID NO: 42)

9.40 Ac-Nle-cyclo(Glu-Lys-D-Phe-Arg-Dab)-Trp-NH ₂ (SEQ ID NO: 43)

9.41 Ac-Nle-ring (Glu-Dab-D-Phe-Arg-Dab)-Trp-NH ₂ (SEQ ID NO: 44)

9.42 Ac-Nle-ring (Glu-Orn-D-Phe-Arg-Dab)-Trp-NH ₂ (SEQ ID NO: 45)

9.43 Ac-Nle-ring (Dap-His-D-Phe-Arg-Dab)-Trp-NH ₂ (SEQ ID NO: 46)

9.44 Ac-Nle-cyclo(Glu-His-D-Phe-Arg-Dab)-NH ₂ (SEQ ID NO:47)

9.45 Ac-Nle-cyclo(Glu-His-D-Phe-Ala-Dab)-NH ₂ (SEQ ID NO:48)

9.46 Ac-Nle-cyclo(Glu-His-D-Phe-Dab)-NH ₂ (SEQ ID NO:49)

9.47 Ac-Nle-cyclo(Glu-His-D-Phe-Gly-Dab)-Trp-NH ₂ (SEQ ID NO:50)

9.48 Ac-Nle-cyclo(Glu-His-D-Phe-Ala-Dab)-Trp-NH ₂ (SEQ ID NO:51)

9.49 Ac-Nle-cyclo(Glu-Ala-D-Phe-Arg-Dab)-Trp-NH ₂ (SEQ ID NO:52)

9.50 Ac-Nle-cyclo(Glu-Arg-D-Phe-Arg-Dab)-Trp-NH ₂ (SEQ ID NO:53)

9.51 Ac-Nle-cyclo(Glu-Cit-D-Phe-Arg-Dab)-Trp-NH ₂ (SEQ ID NO:54)

9.52 Ac-Nle-cyclo(Glu-His-D-Phe-Arg-Dab)-Lys-NH ₂ (SEQ ID NO:55)

9.53 Ac-Nle-cyclo(Glu-Lys-D-Phe-Arg-Dab)-Trp-NH ₂ (SEQ ID NO:56)

9.54 Ac-Nle-cyclo(Glu-Dab-D-Phe-Arg-Dab)-Trp-NH ₂ (SEQ ID NO:57)

9.55 Ac-Nle-ring (Glu-Orn-D-Phe-Arg-Dab)-Trp-NH ₂ (SEQ ID NO:58)

9.56 Ac-Nle-cyclo(Glu-Orn-D-Phe-Arg-Dab)-NH ₂ (SEQ ID NO:59)

9.57 Ac-Nle-cyclo(Glu-Orn-D-Phe(2-Cl)-Arg-Dab)-NH ₂ (SEQ ID NO:60)

9.58 Ac-Nle-cyclo(Glu-Orn-D-Phe(3-Cl)-Arg-Dab)-NH ₂ (SEQ ID NO:61)

9.59 Ac-Nle-cyclo(Glu-Orn-D-Phe(4-Cl)-Arg-Dab)-NH ₂ (SEQ ID NO:62)

9.60 Ac-Nle-cyclo(Glu-Orn-D-Phe(2-F)-Arg-Dab)-NH ₂ (SEQ ID NO:63)

9.61 Ac-Nle-ring (Glu-Orn-D-Phe(4-F)-Arg-Dab)-NH ₂ (SEQ ID NO: 64)

9.62 Ac-Nle-ring (Glu-Orn-D-Phe(3,4-F)-Arg-Dab)-NH ₂ (SEQ ID NO:65)

9.63 Ac-Nle-ring (Glu-Orn-D-Phe(4-Me)-Arg-Dab)-NH ₂ (SEQ ID NO:66)

9.64 Ac-Nle-ring (Glu-Orn-D-Phe(4-OMe)-Arg-Dab)-NH ₂ (SEQ ID NO:67)

9.65 Ac-Nle-cyclo(Glu-Pro-D-Phe-Arg-Dab)-NH ₂ (SEQ ID NO:68)

9.66 Ac-Nle-cyclo(Glu-Pro-D-Phe-Arg-Dab)-Trp-NH ₂ (SEQ ID NO:69)

Although the invention has been described with particular reference to these preferred embodiments, other embodiments are possible to achieve the same result. Variations and modifications of the present invention will be apparent to those skilled in the art and it is intended to cover all such modifications and equivalents. The entire disclosures of all references, applications, patents and publications cited above are hereby incorporated by reference. the

Claims (25)

1. A cyclic peptide of formula (I):

All enantiomers, stereoisomers or diastereomers thereof, or a pharmaceutically acceptable salt of any of the foregoing compounds are included. in: R ₁ is -H, -NH-R ₁₀ , -NH-R ₁₀ -R ₁₁ or -NH-R ₁₁ ; R ₂ is -CH- or -N-; R ₃ is -H, -CH ₃ or -CH ₂ -, and if R ₃ is -CH ₂ -, it forms a ring with R ₄ having the general structure

R ₄ is -H, if R ₃ is -CH ₂ -, R ₄ is -(CH ₂ ) _z -, and if R ₄ is -(CH ₂ ) _z- , it forms the ring with R ₃ where -( Any H in CH ₂ ) _z - is optionally substituted with R ₁₂ , or R ₄ is -(CH ₂ ) _w -R ₁₃ -(CH ₂ ) _w -R ₁₄ , where any H in (CH ₂ ) _w optionally substituted with -(CH ₂ ) _w -CH ₃ ; R ₅ is -(CH2) _w -R ₁₅ ; R ₆ is -H, -CH ₃ or -CH ₂ -, and if R ₆ is -CH ₂ -, it forms a ring with the general structure with R ₇

If R ₆ is -CH ₂ -, R ₇ is -(CH ₂ ) _z -, and if R ₇ is -(CH ₂ ) _z -, it forms the ring with R ₆ , or R ₇ is -(CH ₂ ) _w -R ₁₆ ; R ₈ is -R ₁₇ -R ₁₈ or -R ₁₈ ; _R9 is -(CH ₂ ) _x -C(=O)-NH-(CH ₂ ) _y -, -(CH ₂ ) _x -NH-C(=O)-(CH ₂ ) _y -, -(CH ₂ ) _x -C(=O)-(CH ₂ ) _z -C(=O)-(CH ₂ ) _y -, -(CH ₂ ) _x -C(=O)-NH-C(=O)-(CH ₂ ) _y -, -(CH ₂ ) _x -NH-C(=O)-NH-(CH ₂ ) _y -, -(CH ₂ ) _x -NH-C(=O)-(CH ₂ ) _z -C(=O)-NH-(CH ₂ ) _y -or -(CH ₂ ) _x -SS-(CH ₂ ) _y -; R ₁₀ is one to three amino acid residues; R ₁₁ is H or a C ₁ to C ₁₇ acyl group, wherein the C ₁ to C ₁₇ includes a straight chain or branched chain alkyl, cycloalkyl, alkylcycloalkyl, aryl or alkylaryl; R ₁₂ is optionally present, and if present, in each instance R ₁₂ is independently -R ₁₃ -(CH ₂ ) _w -R ₁₄ ; R ₁₃ is optionally present, and if present, in each instance R ₁₃ is independently -O-, -S-, -NH-, -S(=O) ₂ -, -S(=O)-, -S(=O) ₂ -NH-, -NH-S(=O) ₂ -, -C(=O)-, -C(=O)-O-, -O-C(=O)-, -NH-C(=O)-O-, -O-C(=O)-NH-, -NH-C(=O)- or -C(=O)-NH-; In each case R ₁₄ is independently -H, -CH ₃ , -N(R _19a )(R _19b ), -NH-(CH ₂ ) _z -N(R _19a )(R _19b ), -NH- CH(=NH)-N(R _19a )(R _19b ), -NH-CH(=O)-N(R _19a )(R _19b ), -O(R _19a ), -(R _19a )(R _19b ), -S(=O) ₂ (R _19a ), -C(=O)-O(R _19a ),

wherein any ring in _R is optionally substituted with one or more ring substituents, and when one or more substituents are present, the substituents are the same or different and are independently hydroxyl, halogen, sulfonamide, alkyl , -O-alkyl, aryl, -O-aryl, C(=O)-OH or C(=O)-N(R _19a )(R _19b ); R ₁₅ is phenyl, naphthyl or pyridyl, optionally substituted with one or more substituents independently selected from halogen, (C ₁ -C ₁₀ )alkyl halides, (C ₁ -C ₁₀ ) Alkyl, (C ₁ -C ₁₀ )alkoxy, (C ₁ -C ₁₀ )alkylthio, aryl, aryloxy, nitro, nitrile, sulfonamide, amino, monosubstituted amino, bis Substituted amino, hydroxy, carboxyl and alkoxycarbonyl groups; R ₁₆ is -H, -N(R _19a )(R _19b ), -NH-(CH ₂ ) _z -N(R _19a )(R _19b ), -NH-CH(=NH)-N(R _19a ) (R _19b ), -NH-CH(=O)-N(R _19a )(R _19b ), -O(R _19a ), a straight or branched C ₁ to C ₁₇ alkyl chain, -C(= O)—N(R _19a )(R _19b ),—S(=O) ₂ (R _19a ), wherein any ring is optionally substituted with one or more optional ring substituents which, when present, are the same or different and are independently hydroxyl, halogen, sulfonamide, alkyl , -O-alkyl, aryl, aralkyl, -O-aralkyl or -O-aryl; R ₁₇ is one to three amino acid residues; R ₁₈ is -OH, -N(R _19a )(R _19b ), -N(R _19a )(CH ₂ ) _w -(C ₁ -C ₇ )cycloalkyl or -O-(CH ₂ ) _w -( C ₁ -C ₇ ) cycloalkyl; R _19a and R _19b are each independently H or a C ₁ to C ₄ linear or branched alkyl chain; in each case w is independently 0 to 5; x is 1 to 5; y is 1 to 5; and z is independently 1 to 5 in each case. 2. The cyclic peptide of claim 1, wherein R ₁₇ is a single amino acid residue of the formula

where R ₂₀

Optionally substituted with one or more ring substituents which, when present, are the same or different and are independently hydroxyl, halogen, sulfonamide, alkyl, -O-alkyl, Aryl or -O-aryl. 3. The cyclic peptide of formula (II) as claimed in claim 2:

4. The cyclic peptide of formula (III) as claimed in claim 3:

wherein in each case R _21a , R _21b and R _21c are independently hydrogen, halogen, (C ₁ -C ₁₀ )alkyl halide, (C ₁ -C ₁₀ )alkyl, (C ₁ -C ₁₀ ) Alkoxy, (C ₁ -C ₁₀ )alkylthio, aryl, aryloxy, nitro, nitrile, sulfonamide, amino, monosubstituted amino, disubstituted amino, hydroxyl, carboxyl or alkoxy- carbonyl. 5. The cyclic peptide of formula (IV) as claimed in claim 4: Wherein R ₂₂ is H or a C ₁ to C ₉ straight or branched chain alkyl, cycloalkyl, alkylcycloalkyl, aryl or alkylaryl. 6. The cyclic peptide of formula (V) as claimed in claim 5:

7. The cyclic peptide of formula (VI) as claimed in claim 4: 8. The cyclic peptide of claim 1, wherein R ₉ is -(CH ₂ ) _x -C(=O)-NH-(CH ₂ ) _y -, wherein x is 4 and y is 3, wherein x is 3 and y is 2, or where x is 2 and y is 1. 9. The cyclic peptide of claim 1, wherein R ₉ is -(CH ₂ ) _x -NH-C(=O)-(CH ₂ ) _y -, wherein x is 1 and y is 2, wherein x is 2 and y is 3, or where x is 3 and y is 4. 10. The cyclic peptide of claim 1, wherein _R3 and _R4 form a ring with the general structure where z is 3. 11. The cyclic peptide of claim 1, wherein _R17 is a single amino acid residue of formula. 12. A pharmaceutical composition comprising a cyclic peptide or a pharmaceutically acceptable salt thereof as claimed in claim 1 and a pharmaceutically acceptable carrier. 13. A method of treating a melanocortin receptor-mediated disease, indication, disorder or syndrome in a human or non-human mammal, comprising administering the pharmaceutical composition of claim 12 step. 14. A treatment for a condition in a human or non-human mammal in response to changes in melanocortin receptor function comprising the step of administering the pharmaceutical composition of claim 12. 15. A cyclic peptide of formula (VII): Z-Xaa ¹ -Xaa ² -Xaa ³ -Xaa ⁴ -Xaa ⁵ -Xaa ⁶ -Xaa ⁷ -Y(VII) or a pharmaceutically acceptable salt thereof, wherein: Z is H or an N-terminal group; Xaa ¹ is optionally present, and if present, it is one to three L- or D-isomer amino acid residues; Xaa ² and Xaa ⁶ are L- or D-isomer amino acids, wherein their side chains include a ring bridge; Xaa ³ is L- or D-Pro, optionally with hydroxyl, halogen, sulfonamide, alkyl, -O-alkyl, aryl, alkyl-aryl, alkyl-O-aryl, alkyl- O-alkyl-aryl or -O-aryl, or Xaa ³ is an L- or D-isomer of an amino acid with a side chain comprising at least one primary, tertiary, alkyl , cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, ether, sulfide or carboxyl; Xaa ⁴ is an L- or D-isomer amino acid having a side chain comprising phenyl, naphthyl or pyridyl, optionally wherein the ring is substituted with one or more substituents, which The radicals are independently selected from halogen, (C ₁ -C ₁₀ )alkyl halide, (C ₁ -C ₁₀ )alkyl, (C ₁ -C ₁₀ )alkoxy, (C ₁ -C ₁₀ )alkylthio, Aryl, aryloxy, nitro, nitrile, sulfonamide, amino, monosubstituted amino, disubstituted amino, hydroxyl, carboxyl and alkoxy-carbonyl; Xaa ⁵ is L- or D-Pro or Xaa ⁵ is an L- or D-isomer amino acid with a side chain comprising at least one primary amine, tertiary amine, guanidine, urea, alkyl, ring Alkyl, cycloheteroalkyl, aryl, heteroaryl or ether; ^Xaa7 is optionally present, and if present, it is one to three L- or D-isomer amino acid residues; and Y is a C-terminal group. 16. The cyclic peptide of claim 15, wherein Xaa ⁴ is D-Phe, optionally substituted with one or more substituents independently selected from halogen, (C ₁ -C ₁₀ ) alkane Halide, (C ₁ -C ₁₀ )alkyl, (C ₁ -C ₁₀ )alkoxy, (C ₁ -C ₁₀ )alkylthio, aryl, aryloxy, nitro, nitrile, sulfonamide, Amino, monosubstituted amino, disubstituted amino, hydroxy, carboxyl and alkoxy-carbonyl. 17. The cyclic peptide of claim 15, wherein one of Xaa ² and Xaa ⁶ is an L- or D-isomer of Asp, hGlu or Glu, and the other of Xaa ² and Xaa ⁶ is Lys , Orn, Dab or one of the L- or D-isomers of Dap. 18. The cyclic peptide of claim 15, wherein each of Xaa ² and Xaa ⁶ is Cys, D-Cys, Pen or D-Pen. 19. The cyclic peptide of claim 15, wherein Xaa ¹ is an amino acid with a side chain comprising a straight or branched chain alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl. 20. The cyclic peptide of claim 15, wherein Xaa ⁷ is an amino acid with a side chain comprising at least one aryl or heteroaryl, optionally substituted with one or more ring substituents, when one or Multiple substituents, when present, are the same or different and are independently hydroxy, halogen, sulfonamide, alkyl, -O-alkyl, aryl or -O-aryl. 21. The cyclic peptide of claim 15, wherein the N-terminal group is a _C1 to _C17 acyl group, wherein the _C1 to _C17 comprises a linear or branched chain alkyl, cycloalkyl, Alkylcycloalkyl, aryl or alkylaryl, a straight or branched C ₁ to C ₁₇ alkyl, aryl, heteroaryl, alkene, alkenyl or aralkyl chain, or an N-acyl straight or branched _C1 to _C17 alkyl, aryl, heteroaryl, alkene, alkenyl or aralkyl chain. 22. The cyclic peptide as claimed in claim 15, wherein Y is a hydroxyl group, an amide, or one to two linear or branched C ₁ to C ₁₇ alkyl, cycloalkyl, aryl, alkylcycloalkyl , aralkyl, heteroaryl, alkene, alkenyl or aralkyl chain substituted amides. 23. The cyclic peptide of claim 15, wherein: Xaa ⁴ is D-Phe, optionally substituted with one or more substituents independently selected from halogen, (C ₁ -C ₁₀ )alkyl halide, (C ₁ -C ₁₀ )alkyl, (C ₁ -C ₁₀ )alkoxy, (C ₁ -C ₁₀ )alkylthio, aryl, aryloxy, nitro, nitrile, sulfonamide, amino, monosubstituted amino, disubstituted amino, hydroxyl , carboxyl and alkoxy-carbonyl. Xaa ⁵ is an L- or D-isomer of Arg, Lys, Orn, Dab or Dap; and Xaa ⁷ is an L- or D-isomer of Trp, Nal 1 or Nal 2. 24. The cyclic peptide of claim 23, wherein Xaa ³ is the L- or D-isomer of His. 25. The cyclic peptide of claim 23, wherein Z is a _C1 to _C7 acyl group and ^Xaa1 is the L- or D-isomer of Nle.